4-azaindole compounds

ABSTRACT

Disclosed are compounds of Formula (I)N-oxides, or salts thereof, wherein G, A, R1, R5, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.

CROSS REFERENCE

This application is a continuation application of U.S. patentapplication Ser. No. 16/910,101, filed Jun. 24, 2020, which is acontinuation application of U.S. patent application Ser. No. 16/695,303,filed Nov. 26, 2019, which is a continuation application of U.S.Non-provisional application Ser. No. 16/222,145, filed Dec. 17, 2018,which claims priority to U.S. Provisional Application Ser. No.62/599,875, filed Dec. 18, 2017, the contents of which are specificallyincorporated fully herein by reference.

The present invention generally relates to 4-azaindole compounds usefulas inhibitors of signaling through Toll-like receptor 7, 8, or 9 (TLR7,TLR8, TLR9) or combinations thereof. Provided herein are 4-azaindolecompounds, compositions comprising such compounds, and methods of theiruse. The invention further pertains to pharmaceutical compositionscontaining at least one compound according to the invention that areuseful for the treatment of conditions related to TLR modulation, suchas inflammatory and autoimmune diseases, and methods of inhibiting theactivity of TLRs in a mammal.

Toll/IL-1 receptor family members are important regulators ofinflammation and host resistance. The Toll-like receptor familyrecognizes molecular patterns derived from infectious organismsincluding bacteria, fungi, parasites, and viruses (reviewed in Kawai, T.et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to thereceptor induces dimerization and recruitment of adaptor molecules to aconserved cytoplasmic motif in the receptor termed the Toll/IL-1receptor (TIR) domain with the exception of TLR3, all TLRs recruit theadaptor molecule MyD88. The IL-1 receptor family also contains acytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewedin Sims, J. E. et al., Nature Rev. Immunol., 10:89-102 (2010)).

Toll-like receptors (TLRs) are a family of evolutionarily conserved,transmembrane innate immune receptors that participate in the first-linedefense. As pattern recognition receptors, the TLRs protect againstforeign molecules, activated by pathogen associated molecular patterns(PAMPs), or from damaged tissue, activated by danger associatedmolecular patterns (DAMPs). A total of 13 TLR family members have beenidentified, 10 in human, that span either the cell surface or theendosomal compartment. TLR7-9 are among the set that are endosomallylocated and respond to single-stranded RNA (TLR7 and TLR8) orunmethylated single-stranded DNA containing cytosine-phosphate-guanine(CpG) motifs (TLR9).

Activation of TLR7/8/9 can initiate a variety of inflammatory responses(cytokine production, B cell activation and IgG production, Type Iinterferon response). In the case of autoimmune disorders, the aberrantsustained activation of TLR7/8/9 leads to worsening of disease states.Whereas overexpression of TLR7 in mice has been shown to exacerbateautoimmune disease, knockout of TLR7 in mice was found to be protectiveagainst disease in lupus-prone MRL/lpr mice. Dual knockout of TLR7 and 9showed further enhanced protection.

As numerous conditions may benefit by treatment involving modulation ofcytokines, IFN production and B cell activity, it is immediatelyapparent that new compounds capable of modulating TLR7 and/or TLR8and/or TLR9 and methods of using these compounds could providesubstantial therapeutic benefits to a wide variety of patients.

The present invention relates to a new class of 4-azaindole compoundsfound to be effective inhibitors of signaling through TLR7/8/9. Thesecompounds are provided to be useful as pharmaceuticals with desirablestability, bioavailability, therapeutic index, and toxicity values thatare important to their drugability.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that are usefulas inhibitors of signaling through Toll-like receptor 7, 8, or 9 and areuseful for the treatment of proliferative diseases, allergic diseases,autoimmune diseases and inflammatory diseases, or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates or prodrugsthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for inhibition of Toll-likereceptor 7, 8, or 9 comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides a method of treating a disease ordisorder associated with Toll-like receptor 7, 8, or 9 activity, themethod comprising administering to a mammal in need thereof, at leastone of the compounds of Formula (I) or salts, solvates, and prodrugsthereof.

The present invention also provides processes and intermediates formaking the compounds of Formula (I) including salts, solvates, andprodrugs thereof.

The present invention also provides at least one of the compounds ofFormula (I) or salts, solvates, and prodrugs thereof, for use intherapy.

The present invention also provides the use of at least one of thecompounds of Formula (I) or salts, solvates, and prodrugs thereof, forthe manufacture of a medicament for the treatment of prophylaxis ofToll-like receptor 7, 8, or 9 related conditions, such as allergicdisease, autoimmune diseases, inflammatory diseases, and proliferativediseases.

The compound of Formula (I) and compositions comprising the compounds ofFormula (I) may be used in treating, preventing, or curing variousToll-like receptor 7, 8, or 9 related conditions. Pharmaceuticalcompositions comprising these compounds are useful for treating,preventing, or slowing the progression of diseases or disorders in avariety of therapeutic areas, such as allergic disease, autoimmunediseases, inflammatory diseases, and proliferative diseases.

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

-   -   N-oxide, or a salt thereof, wherein:    -   G is:

-   -   (iv) a 9-membered heterocyclic ring selected from:

-   -   (v) 10-membered heterocyclic ring selected from:

-   -   A is:    -   (i) —O-L₁-R₆;    -   (ii) —NR₇R₈;    -   (iii) -L₂-C(O)NR₉R₁₀;    -   (iv) —(CR_(x)R_(x))₁₋₃R₁₁, C₁₋₃ aminoalkyl,        —(CR_(x)R_(x))₁₋₃NR_(x)C(O)R₁₁,        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)O(CH₂)₁₋₂(piperidinyl), or        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);    -   —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom        to which they are attached form a cyclic group selected from        azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,        diazepanyl, azaspiro[3.3]heptanyl, diazaspiro[4.5]decanonyl,        morpholinyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl,        piperidinyl, pyrrolidinyl, and quinuclidinyl, each substituted        with zero to 4 R_(12a);    -   (vi) —CR_(x)═CR_(x)(piperidinyl); or    -   (vii) an aromatic group selected from        [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,        imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl,        phenyl, pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl,        pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl,        quinolinyl, quinoxalinyl,        tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,        tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,        tetrahydrothiazolo[5,4-c]pyridinyl,        tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,        thiooxadiazolyl, and triazolyl, each substituted with zero to 2        R_(14a) and zero to 3 R_(14b);    -   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,        —(CR_(x)R_(x))₁₋₂O—, —CR_(x)R_(x)C(O)—,        —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—,        —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, or        —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, or    -   L₂ is a bond or —(CR_(x)R_(x))₁₋₃—;    -   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃        hydroxyalkyl, C₁₋₃ hydroxy-fluoroalkyl, —CR_(v)═CH₂, C₃₋₆        cycloalkyl, —CH₂(C₃₋₆ cycloalkyl), —C(O)O(C₁₋₃ alkyl), or        tetrahydropyranyl;    -   each R₂ is independently halo, —CN, —OH, —NO₂, C₁₋₄ alkyl, C₁₋₂        fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃        aminoalkyl, —O(CH₂)₀₋₂OH, —(CH₂)₀₋₄O(C₁₋₄ alkyl), C₁₋₃        fluoroalkoxy, —(CH₂)₁₋₄O(C₁₋₃ alkyl), —O(CH₂)₁₋₂OC(O)(C₁₋₃        alkyl), —O(CH₂)₁₋₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl),        —(CH₂)₀₋₂C(O)NR_(y)R_(y), —C(O)NR_(x)(C₁₋₅ hydroxyalkyl),        —C(O)NR_(x)(C₂₋₆ alkoxyalkyl), —C(O)NR_(x)(C₃₋₆ cycloalkyl),        —NR_(y)R_(y), —NR_(y)(C₁₋₃ fluoroalkyl), —NR_(y)(C₁₋₄        hydroxyalkyl), —NR_(x)CH₂(phenyl), —NR_(x)S(O)₂(C₃₋₆        cycloalkyl), —NR_(x)C(O)(C₁₋₃ alkyl), —NR_(x)CH₂(C₃₋₆        cycloalkyl), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl), —(CH₂)₀₋₂(C₃₋₆        cycloalkyl), —(CH₂)₀₋₂(phenyl), morpholinyl,        dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl,        methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or        —C(O)(thiazolyl);    -   R_(2a) is C₁₋₆ alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃        aminoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,        —(CH₂)₁₋₃C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),        tetrahydrofuranyl, tetrahydropyranyl, or phenyl;    -   each R_(2b) is independently H, halo, —CN, —NR_(x)R_(x), C₁₋₆        alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,        —(CH₂)₀₋₂O(C₁₋₃alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆        cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),        —CR_(x)═CR_(x)R_(x), or —CR_(x)═CH(C₃₋₆ cycloalkyl);    -   R_(2c) is R_(2a) or R_(2b);    -   R_(2d) is R_(2a) or R_(2b); provided that one of R_(2c) and        R_(2d) is R_(2a), and the other of R_(2c) and R₂ is R_(2b);    -   each R₅ is independently F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂        fluoroalkyl, or —OCH₃;    -   R₆ is:        -   (i) C₁₋₃ alkyl, —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₃OH,            —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), or            —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂CHFCR_(x)R_(x)OH; or        -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,            azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,            diazaspiro[3.5]nonanyl, morpholinyl, tetrahydrofuranyl,            tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl,            piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl,            each substituted with zero to 3 R_(6a);    -   each R_(6a) is independently F, Cl, —OH, —CN, C₁₋₆ alkyl, C₁₋₄        fluoroalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl),        —NR_(y)R_(y), —(CH₂)₁₋₂NR_(x)R_(x), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₃        alkyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),        —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), oxetanyl, tetrahydrofuranyl,        tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,        isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);    -   R₇ is:        -   (i) R_(7a), —CH₂R_(7a), —(CH₂)₁₋₃NR_(y)R_(y),            —(CH₂)₁₋₃NR_(x)C(O)(CH₂)₁₋₂NR_(y)R_(y), —C(O)R_(7a),            —C(O)CH(NH₂)R_(7a), —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄            alkyl), —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂,            or —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or        -   (ii) C₃₋₆ cycloalkyl substituted with one substituent            selected from —NR_(x)(CH₂)₂₋₃NR_(y)R_(y),            —NR_(x)(methylpiperidinyl), —NR_(x)(CH₂)₂₋₃(morpholinyl),            dimethylamino piperidinyl, and piperazinyl substituted with            a substituent selected from C₁₋₄ alkyl, —C(O)CH₃,            —(CH₂)₁₋₂OCH₃, —CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl),            C₃₋₆ cycloalkyl, pyridinyl, and methylpiperidinyl;    -   R_(7a) is azaspiro[3.5]nonanyl, C₃₋₆ cycloalkyl,        diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, diazepanonyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrrolidinonyl, pyrrolidinyl, or pyrrolyl, each substituted with        zero to 1 substituent selected from C₁₋₃ alkyl, —NH₂,        methylpiperidinyl, methylpyrrolidinyl, —OCH₂CH₂(pyrrolidinyl),        and —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from        —CH₃;    -   R_(7b) is:        -   (i) —OH, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl,            C₁₋₃ aminoalkyl, —(CH₂)₂₋₃C≡CH, —(CR_(x)R_(x))₁₋₂O(C₁₋₂            alkyl), —(CH₂)₁₋₃S(O)₂(C₁₋₂ alkyl), —(CH₂)₀₋₃NR_(x)R_(y),            —(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(y)R_(y), —NR_(x)(C₁₋₄            hydroxyalkyl), —NR_(y)(C₁₋₂ cyanoalkyl), —N(C₁₋₂            cyanoalkyl)₂, —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄            hydroxyfluoroalkyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),            —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),            —N((CH₂)₁₋₂C(O)NR_(x)R_(x))₂, —NR_(x)(CH₂)₁₋₂S(O)₂(C₁₋₂            alkyl), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),            —NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),            —NR_(x)(CH₂CH₂S(O)₂CH₃),            —(CH₂)₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),            —O(CH₂)₁₋₃NR_(x)R_(x), —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y),            —C(O)(CR_(x)R_(x))₁₋₂NR_(y)(C₁₋₄ hydroxyalkyl),            —C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃),            —S(O)₂CH₂CH₂N(CH₃)₂, —(CH₂)₁₋₂R_(7d), —NR_(x)R_(7d),            —NR_(x)(CH₂)₁₋₂R_(7d)), —NR_(7d)R_(7d), —N((CH₂)₁₋₂R_(7d))₂,            —OR_(7d), —C(O)R_(7d), —C(O)(CR_(x)R_(x))₁₋₂R_(7d), or            —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(7d); or        -   (ii) azepanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,            dioxotetrahydrothiopyranyl, dioxothiomorpholinyl,            morpholinyl, oxaazaspiro[3.3]heptanyl,            oxaazaspiro[4.3]octanyl, oxetanyl, piperazinonyl,            piperazinyl, piperidinyl, pyridinyl, pyrimidinyl,            pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydroisoquinolinyl, tetrahydropyranyl, or thiadiazolyl,            each substituted with zero to 1 R_(8a) and zero to 3 R_(8b);    -   each R_(7c) is independently F, Cl, —CN, C₁₋₂ alkyl, —CF₃, or        —CH₂CN;    -   R_(7d) is azaspiro[3.5]nonanyl, azetidinyl,        bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,        dioxothiaazaspiro[3.3]heptanyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,        oxaazaspiro[4.4]nonyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,        pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,        thiadiazolyl, or triazolyl, each substituted with zero to 2        substituents independently selected from F, —OH, C₁₋₃ alkyl,        C₁₋₂ hydroxyalkyl, C₁₋₂ alkoxy, —NR_(x)R_(x), —C(O)CH₃,        —S(O)₂CH₃, methylpiperidinyl, methylpyrrolidinyl,        tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and        —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;    -   R₈ is H or C₁₋₃ alkyl;    -   or R₇ and R₈ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidinyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl,        diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.1]octanyl,        azaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl,        diazaspiro[3.3]heptanyl, diazepanonyl, diazepanyl,        diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, imidazolyl,        imidazolidinonyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl,        oxadiazabicyclo[3.3.1]nonanyl, piperazinyl, piperazinonyl,        piperidinyl, pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein        said heterocyclic ring is substituted with zero to 1 R_(7b) and        zero to 2 R_(7c);    -   R_(8a) is —OH, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl,        —(CH₂)₁₋₂O(C₁₋₃ alkyl), C₁₋₂ alkoxy, —C(O)(C₁₋₃ alkyl),        —C(O)O(C₁₋₂ alkyl), —(CH₂)₁₋₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₃(methyl        phenyl), —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₃(methylpyrazolyl),        —(CH₂)₁₋₃(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl,        methylpiperidinyl, pyridinyl, or pyrimidinyl;    -   each R_(8b) is independently F, Cl, —CN, C₁₋₃ alkyl, or —CF₃;    -   R₉ is C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆        hydroxy fluoroalkyl, C₁₋₃ aminoalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl),        —(CH₂)₁₋₃NR_(x)R_(x), —(CH₂)₁₋₂C(O)NR_(x)R_(x),        —(CH₂)₁₋₃S(O)₂OH, —(CR_(x)R_(x))₁₋₃NR_(x)S(O)₂(C₁₋₂ alkyl), or        —(CH₂)₀₋₃R_(9a);    -   R_(9a) is C₃₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,        piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,        thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted        with zero to 3 substituents independently selected from F, Cl,        —OH, C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ hydroxy fluoroalkyl,        C₁₋₃ aminoalkyl, —NR_(y)R_(y), oxetanyl, phenyl, piperazinyl,        piperidinyl, and pyrrolidinyl;    -   R₁₀ is H, C₁₋₄ alkyl, —(CH₂)₁₋₃O(C₁₋₂ alkyl), or C₃₋₆        cycloalkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from        azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,        diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,        diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,        indolinyl, morpholinyl, octahydropyrrolo[3,4-c] pyrrolyl,        piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each        substituted with zero to 3 R_(10a);    -   each R_(10a) is independently C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl,        —(CH₂)₁₋₃O(C₁₋₃ alkyl), —(CH₂)₁₋₃NR_(x)R_(x),        —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂(methyltriazolyl),        —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl), —C(O)(C₁₋₂ alkyl),        —C(O)NR_(y)R_(y), —C(O)CH₂NR_(y)R_(y), —NR_(y)R_(y),        —NHC(O)(C₁₋₃ alkyl), —C(O)(furanyl), —O(piperidinyl),        —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,        piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,        isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,        pyrimidinyl, or dihydrobenzo[d]imidazolonyl;    -   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,        hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,        piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with        zero to 3 substituents independently selected from halo, —CN,        C₁₋₄ alkyl, C₁₋₃ aminoalkyl, —(CH₂)₁₋₂(methyloxetanyl),        —(CH₂)₁₋₂ (triazolyl), —(CH₂)₁₋₂(phenyl), —C(O)CH₂NR_(x)R_(x),        C₁₋₅ hydroxyalkyl, —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₃        alkyl), —(CH₂)₁₋₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl,        and tetrahydropyranyl;    -   each R_(12a) is independently F, Cl, —OH, C₁₋₆ alkyl, C₁₋₄        fluoroalkyl, C₁₋₄ cyanoalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃        alkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),        —(CH₂)₁₋₂NR_(x)HS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₃        alkoxy, —NR_(y)R_(y), —NR_(x)(C₁₋₄ fluoroalkyl), —NR_(x)(C₁₋₂        cyanoalkyl), —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),        —NR_(x)(CR_(x)R_(x)CR_(x)R_(x))O(C₁₋₃ alkyl),        —NR_(x)(CH₂C(O)NR_(x)R_(x)), —NR_(x)(C₁₋₃ alkoxy),        —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl), —NR_(x)C(O)CH₃, —NR_(x)C(O)(C₁₋₂        fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),        —NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄        hydroxyalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂(C₁₋₂        alkyl), —C(O)(C₁₋₅ alkyl), —C(O)(CH₂)₁₋₃O(C₁₋₂ alkyl),        —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y), R_(12b), —CR_(x)R_(x)R_(12b),        —C(O)R_(12b), —C(O)CR_(x)R_(x)NR_(x)R_(12b), —C(O)NR_(x)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),        —NR_(x)CR_(x)R_(x)R_(12b), —N(CH₂CN)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)NR_(x)CH₂R_(12b),        —NR_(x)CR_(x)R_(x)C(O)NR_(x)R_(12b), or —OR_(12b); or two        R_(12a) and the carbon atom to which they are attached form C═O;    -   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,        diazabicyclo[2.2.1]heptanyl, dioxolanyl,        dioxothiaazaspiro[3.3]heptanyl, dioxidotetrahydrothiopyranyl,        dioxidothiomorpholinyl, imidazolyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,        oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,        oxaazaspiro[4.4]nonanyl, oxetanyl, phenyl, piperazinyl,        piperazinonyl, piperidinyl, pyridinyl, pyrrolidinyl,        quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, or        triazolyl, each substituted with zero to 4 substituents        independently selected from F, Cl, —OH, C₁₋₄ alkyl, C₁₋₃        fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₄ alkoxy,        —(CH₂)₁₋₂O(C₁₋₃ alkyl), —NR_(x)R_(x), —C(O)NR_(x)R_(x), and        —(CR_(x)R_(x))₀₋₁S(O)₂(C₁₋₃ alkyl);    -   each R_(14a) is independently is:        -   (i) H, halo, —OH, C₁₋₆ alkyl, C₁₋₂₃ fluoroalkyl, C₁₋₄            hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl),            —CR_(x)R_(x)NR_(y)R_(y), —CR_(x)R_(x)NR_(x)(C₁₋₃            cyanoalkyl), —CR_(x)R_(x)NR_(x)((CH₂)₁₋₂O(C₁₋₂ alkyl)),            —CR_(x)R_(x)N((CH₂)₁₋₂OCH₃)₂,            —CR_(x)R_(x)NR_(x)(CH₂C≡CR_(x)),            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃NR_(x)R_(x),            —(CR_(x)R_(x))₁₋₃CR_(x)R_(x)NR_(x)R_(x),            —CR_(x)(NH₂)(CH₂)₁₋₄NR_(x)R_(x),            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH,            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃S(O)₂OH,            —CR_(x)R_(x)C(O)NR_(x)R_(x), —NR_(x)R_(y),            —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), NR_(x)C(O)(C₁₋₃ alkyl),            —NR_(x)C(O)(C₁₋₃ fluoroalkyl), —NR_(x)C(O)O(C₁₋₃ alkyl),            —NR_(x)C(O)(CH₂)₁₋₃NR_(x)R_(x),            —NR_(x)CH₂C(O)CH₂NR_(x)R_(x), —C(O)(C₁₋₃ alkyl),            —C(O)(CR_(x)R_(x))₁₋₃OH, —C(O)CR_(x)R_(x)NR_(x)R_(x),            —C(O)NR_(x)R_(x), —C(O)NR_(x)(C₁₋₂ cyanoalkyl),            —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),            —C(O)N(CH₂CH₃)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),            —C(O)NR_(x)(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),            —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)C(O)(C₁₋₂ alkyl),            —O(CR_(x)R_(x))₁₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or            —C(O)(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl);        -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,            azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl,            cyclohexyl, diazepanyl, morpholinyl, phenyl, piperazinyl,            piperidinyl, pyrazolyl, pyridinyl, pyrrolidinonyl,            quinolinyl, quinuclidinyl, tetrahydroisoquinolinyl,            tetrahydropyridinyl, or thiazolidinyl, each substituted with            zero to 2 substituents independently selected from C₁₋₄            alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —NR_(x)R_(x),            —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),            —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl),            —CH₂C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, —CH₂(phenyl),            —CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),            —CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl,            and pyridinyl; or        -   (iii) -L₃-R_(14c);    -   each R_(14b) is F, Cl, —OH, —H₃, or —OCH₃;    -   R_(14c) is adamantanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,        diazepanyl, imidazolyl, indolyl, morpholinyl,        octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, pyrrolyl, triazolyl, or tetrazolyl, each        substituted with zero to 1 substituent selected from F, —OH,        C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —NR_(x)R_(y), —NR_(x)C(O)CH₃,        —C(O)(C₁₋₂ alkyl), —C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂,        —C(O)(tetrahydrofuranyl), —C(O)O(C₁₋₂ alkyl),        —CH₂C(O)NR_(x)R_(y), morpholinyl, methylpiperidinyl, pyrazinyl,        pyridinyl, and pyrrolidinyl;    -   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NR_(x)—,        —C(O)—, —C(O)NR_(x)(CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—,        —NR_(x)CH₂—, —NR_(x)CH₂C(O)—, or —O(CH₂)₀₋₂—;    -   R_(v) is H, C₁₋₂ alkyl, or C₁₋₂ fluoroalkyl;    -   each R_(x) is independently H or —CH₃;    -   each R_(y) is independently H or C₁₋₆ alkyl;    -   n is zero, 1, or 2; and    -   p is zero, 1, 2, 3, or 4.

The second aspect of the present invention provides at least onecompound of Formula (I), N-oxide, or a salt thereof, wherein:

-   -   G is defined in the first aspect;    -   A is:    -   (i) —O-L₁-R₆;    -   (ii) —NR₇R₈;    -   (iii) -L₂-C(O)NR₉R₁₀;    -   (iv) —(CR_(x)R_(x))₁₋₃R₁₁, C₁₋₃ aminoalkyl,        —(CR_(x)R_(x))₁₋₃NR_(x)C(O)R₁₁,        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)O(CH₂)₁₋₂(piperidinyl), or        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);    -   (v) —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon        atom to which they are attached form a cyclic group selected        from azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇        cycloalkyl, diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,        pyrrolidinyl, and quinuclidinyl, each substituted with zero to 4        R_(12a);    -   (vi) —CR_(x)═CR_(x)(piperidinyl); or    -   (vii) an aromatic group selected from        [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,        imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl,        phenyl, pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl,        pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl,        quinolinyl, quinoxalinyl,        tetrahydro[1,2,4]triazolo[1,5-a]pyrazinyl,        tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,        tetrahydrothiazolo[5,4-c]pyridinyl,        tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,        thiooxadiazolyl, and triazolyl, each substituted with zero to 2        R_(14a) and zero to 3 R_(14b);    -   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,        —(CR_(x)R_(x))₁₋₂O—, —CR_(x)R_(x)C(O)—,        —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—,        —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, or        —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—;    -   L₂ is a bond or —(CR_(x)R_(x))₁₋₃—;    -   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃        hydroxyalkyl, C₁₋₃ hydroxy-fluoroalkyl, —CR_(v)═CH₂, C₃₋₆        cycloalkyl, —CH₂(C₃₋₆ cycloalkyl), —C(O)O(C₁₋₃ alkyl), or        tetrahydropyranyl;    -   each R₂ is independently halo, —CN, —OH, —NO₂, C₁₋₄ alkyl, C₁₋₂        fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃        aminoalkyl, —O(CH₂)₁₋₂OH, —(CH₂)₀₋₄O(C₁₋₄ alkyl), C₁₋₃        fluoroalkoxy, —(CH₂)₁₋₄O(C₁₋₃ alkyl), —O(CH₂)₁₋₂OC(O)(C₁₋₃        alkyl), —O(CH₂)₁₋₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl),        —(CH₂)₀₋₂C(O)NR_(y)R_(y), —C(O)NR_(x)(C₁₋₅ hydroxyalkyl),        —C(O)NR_(x)(C₂₋₆ alkoxyalkyl), —C(O)NR_(x)(C₃₋₆ cycloalkyl),        NR_(y)R_(y), —NR_(y)(C₁₋₃ fluoroalkyl), —NR_(y)(C₁₋₄        hydroxyalkyl), —NR_(x)CH₂(phenyl), —NR_(x)S(O)₂(C₃₋₆        cycloalkyl), —NR_(x)C(O)(C₁₋₃ alkyl), —NR_(x)CH₂(C₃₋₆        cycloalkyl), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl), —(CH₂)₀₋₂(C₃₋₆        cycloalkyl), —(CH₂)₀₋₂(phenyl), morpholinyl,        dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl,        methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or        —C(O)(thiazolyl);    -   R_(2a) is C₁₋₆ alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃        aminoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,        —(CH₂)₁₋₃C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),        tetrahydrofuranyl, tetrahydropyranyl, or phenyl;    -   each R_(2b) is independently H, halo, —CN, —NR_(x)R_(x), C₁₋₆        alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,        —(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆        cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),        —CR_(x)═CR_(x)R_(x), or —CR_(x)═CH(C₃₋₆ cycloalkyl);    -   R_(2c) is R_(2a) or R_(2b);    -   R_(2d) is R_(2a) or R_(2b); provided that one of R_(2c) and        R_(2d) is R_(2a), and the other of R_(2c) and R₂ is R_(2b);    -   each R₅ is independently F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂        fluoroalkyl, or —OCH₃;    -   R₆ is:        -   (i) —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₃OH,            —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), or            —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂CHFCR_(x)R_(x)OH; or        -   (ii) azabicyclo[3.2 1]octanyl, azaspiro[5.5]undecanyl,            azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,            diazaspiro[3.5]nonanyl, morpholinyl, tetrahydrofuranyl,            tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl,            piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl,            each substituted with zero to 3 R_(6a);    -   each R_(6a) is independently F, Cl, —OH, —CN, C₁₋₆ alkyl, C₁₋₄        fluoroalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl),        —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₃        alkyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),        —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), oxetanyl, tetrahydrofuranyl,        tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,        isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);    -   R₇ is:        -   (i) R_(7a), —CH₂R_(7a), —C(O)R_(7a), —C(O)CH(NH₂)R_(7a),            —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄ alkyl),            —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or            —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or        -   (ii) C₃₋₆ cycloalkyl substituted with one substituent            selected from —NR_(x)(CH₂)₂₋₃NR_(y)R_(y),            —NR_(x)(methylpiperidinyl), —NR_(x)(CH₂)₂₋₃(morpholinyl),            dimethylamino piperidinyl, and piperazinyl substituted with            a substituent selected from C₁₋₄ alkyl, —C(O)CH₃,            —(CH₂)₁₋₂OCH₃, —CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl),            C₃₋₆ cycloalkyl, pyridinyl, and methylpiperidinyl;    -   R_(7a) is azaspiro[3.5]nonanyl, C₃₋₆ cycloalkyl,        diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, diazepanonyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrrolidinonyl, pyrrolidinyl, or pyrrolyl, each substituted with        zero to 1 substituent selected from C₁₋₃ alkyl, —NH₂,        methylpiperidinyl, methylpyrrolidinyl, —OCH₂CH₂(pyrrolidinyl),        and —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from        —CH₃;    -   R_(7b) is:        -   (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₂₋₃C≡CH,            —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),            —(CH₂)₀₋₃NR_(x)R_(y), —CH₂C(O)NR_(x)R_(x), —NR_(x)(C₁₋₄            hydroxyalkyl), —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂            fluoroalkyl), —NR_(x)(C₂₋₄ hydroxyfluoroalkyl),            —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),            —NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),            —O(CH₂)₁₋₃NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d),            —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or        -   (ii) azepanyl, azetidinyl, diazepanyl, dioxothiomorpholinyl,            morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl,            piperazinonyl, piperazinyl, piperidinyl, pyridinyl,            pyrrolidinonyl, pyrrolidinyl, or tetrahydroisoquinolinyl,            each substituted with zero to 1 R_(8a) and zero to 3 R_(8b);    -   each R_(7c) is independently F, Cl, —CN, C₁₋₂ alkyl, —CF₃, or        —CH₂CN;    -   R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆        cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl,        pyrazolyl, pyrrolidinyl, tetrahydrofuranyl, or        tetrahydropyranyl, each substituted with zero to 1 substituent        selected from C₁₋₃ alkyl, —NR_(x)R_(x), —C(O)CH₃,        methylpiperidinyl, methylpyrrolidinyl, tetramethylpiperidinyl,        —OCH₂CH₂(pyrrolidinyl), and —OCH₂CH₂NHCH₂CH₃; and zero to 4        substituents selected from —CH₃;    -   R₈ is H or C₁₋₃ alkyl;    -   or R₇ and R₈ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidinyl,        diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,        diazaspiro[5.5]undecanyl, imidazolyl, imidazolidinonyl,        octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,        pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein said        heterocyclic ring is substituted with zero to 1 R_(7b) and zero        to 2 R_(7c);    -   R_(8a) is —OH, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, hydroxyalkyl,        —(CH₂)₁₋₂O(C₁₋₃ alkyl), —C(O)(C₁₋₃ alkyl), —(CH₂)₁₋₂(C₃₋₆        cycloalkyl), —(CH₂)₁₋₃(methyl phenyl), —(CH₂)₁₋₃(pyrrolidinyl),        —(CH₂)₁₋₃(methylpyrazolyl), —(CH₂)₁₋₃(thiophenyl), —NR_(x)R_(x),        C₃₋₆ cycloalkyl, methylpiperidinyl, pyridinyl, or pyrimidinyl;    -   each R_(8b) is independently F, Cl, —CN, C₁₋₃ alkyl, or —CF₃;    -   R_(9a) is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ hydroxy        fluoroalkyl, C₁₋₃ aminoalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl),        —(CH₂)₁₋₃NR_(x)R_(x), —(CH₂)₁₋₂C(O)NR_(x)R_(x),        —(CH₂)₁₋₃S(O)₂OH, —(CR_(x)R_(x))₁₋₃NR_(x)S(O)₂(C₁₋₂ alkyl), or        —(CH₂)₀₋₃R_(9a);    -   R_(9a) is C₃₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,        piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,        thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted        with zero to 3 substituents independently selected from F, Cl,        —OH, C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ hydroxy fluoroalkyl,        aminoalkyl, —NR_(y)R_(y), oxetanyl, phenyl, piperazinyl,        piperidinyl, and pyrrolidinyl;    -   R₁₀ is H, C₁₋₄ alkyl, —(CH₂)₁₋₃O(C₁₋₂ alkyl), or C₃₋₆        cycloalkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from        azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,        diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,        diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,        indolinyl, morpholinyl, octahydropyrrolo[3,4-c] pyrrolyl,        piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each        substituted with zero to 3 R_(10a);    -   each R_(10a) is independently C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl,        —(CH₂)₁₋₃O(C₁₋₃ alkyl), —(CH₂)₁₋₃NR_(x)R_(x),        —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂(methyltriazolyl),        —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl), —C(O)(C₁₋₂ alkyl),        —C(O)NR_(y)R_(y), —C(O)CH₂NR_(y)R_(y), —NR_(y)R_(y),        —NHC(O)(C₁₋₃ alkyl), —C(O)(furanyl), —O(piperidinyl),        —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,        piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,        isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,        pyrimidinyl, or dihydrobenzo[d]imidazolonyl;    -   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,        hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,        piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with        zero to 3 substituents independently selected from halo, —CN,        C₁₋₄ alkyl, C₁₋₃ aminoalkyl, —(CH₂)₁₋₂(phenyl),        —C(O)CH₂NR_(x)R_(x), C₁₋₅ hydroxyalkyl,        —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₃ alkyl),        —(CH₂)₁₋₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl, and        tetrahydropyranyl;    -   each R_(12a) is independently F, Cl, —OH, C₁₋₆ alkyl, C₁₋₄        fluoroalkyl, C₁₋₄ cyanoalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃        alkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),        —(CH₂)₁₋₂NR_(x)HS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₃        alkoxy, —NR_(y)R_(y), —NR_(x)(C₁₋₄ fluoroalkyl), —NR_(x)(C₁₋₂        cyanoalkyl), —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),        —NR_(x)(CR_(x)R_(x)CR_(x)R_(x))O(C₁₋₃ alkyl),        —NR_(x)(CH₂C(O)NR_(x)R_(x)), —NR_(x)(C₁₋₃ alkoxy),        —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl), —NR_(x)C(O)CH₃, —NR_(x)C(O)(C₁₋₂        fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),        —NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄        hydroxyalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂(C₁₋₂        alkyl), —C(O)(C₁₋₅ alkyl), —C(O)(CH₂)₁₋₃O(C₁₋₂ alkyl),        —C(O)CR_(x)R_(x)NR_(y)R_(y), R_(12b), —CR_(x)R_(x)R_(12b),        —C(O)R_(12b), —C(O)CR_(x)R_(x)NR_(x)R_(12b), —C(O)NR_(x)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),        —NR_(x)CR_(x)R_(x)R_(12b), —N(CH₂CN)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)NR_(x)CH₂R_(12b),        —NR_(x)CR_(x)R_(x)C(O)NR_(x)R_(12b), or —OR_(12b); or two        R_(12a) and the carbon atom to which they are attached form C═O;    -   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,        diazabicyclo[2.2.1]heptanyl, dioxolanyl,        dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl,        imidazolyl, morpholinyl, octahydrocyclopenta[c]pyrrolyl,        octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl,        oxetanyl, phenyl, piperazinyl, piperazinonyl, piperidinyl,        pyridinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,        tetrahydropyranyl, or triazolyl, each substituted with zero to 4        substituents independently selected from F, Cl, —OH, C₁₋₄ alkyl,        C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₄        alkoxy, —(CH₂)₁₋₂O(C₁₋₃ alkyl), —NR_(x)R_(x), —C(O)NR_(x)R_(x),        and —(CR_(x)R_(x))₀₋₁S(O)₂(C₁₋₃ alkyl);    -   each R_(14a) is independently is:        -   (i) H, halo, —OH, C₁₋₆ alkyl, C₁₋₂₃ fluoroalkyl, C₁₋₄            hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl),            —CR_(x)R_(x)NR_(y)R_(y), —CR_(x)R_(x)NR_(x)(C₁₋₃            cyanoalkyl), —CR_(x)R_(x)NR_(x)((CH₂)₁₋₂O(C₁₋₂ alkyl)),            —CR_(x)R_(x)N((CH₂)₁₋₂OCH₃)₂,            —CR_(x)R_(x)NR_(x)(CH₂C≡CR_(x)),            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃NR_(x)R_(x),            —(CR_(x)R_(x))₁₋₃CR_(x)R_(x)NR_(x)R_(x),            —CR_(x)(NH₂)(CH₂)₁₋₄NR_(x)R_(x),            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH,            —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃S(O)₂OH,            —CR_(x)R_(x)C(O)NR_(x)R_(x), —NR_(x)R_(y),            —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)C(O)(C₁₋₃ alkyl),            —NR_(x)C(O)(C₁₋₃ fluoroalkyl), —NR_(x)C(O)O(C₁₋₃ alkyl),            —NR_(x)C(O)(CH₂)₁₋₃NR_(x)R_(x),            —NR_(x)CH₂C(O)CH₂NR_(x)R_(x), —C(O)(C₁₋₃ alkyl),            —C(O)(CR_(x)R_(x))₁₋₃OH, —C(O)CR_(x)R_(x)NR_(x)R_(x),            —C(O)NR_(x)R_(x), —C(O)NR_(x)(C₁₋₂ cyanoalkyl),            —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),            —C(O)N(CH₂CH₃)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),            —C(O)NR_(x)(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),            —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)C(O)(C₁₋₂ alkyl),            —O(CR_(x)R_(x))₁₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or            —C(O)(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl);        -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,            azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl,            cyclohexyl, diazepanyl, morpholinyl, phenyl, piperazinyl,            piperidinyl, pyrazolyl, pyridinyl, pyrrolidinonyl,            quinolinyl, quinuclidinyl, tetrahydroisoquinolinyl,            tetrahydropyridinyl, or thiazolidinyl, each substituted with            zero to 2 substituents independently selected from C₁₋₄            alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —NR_(x)R_(x),            —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂-2 alkyl),            —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl),            —CH₂C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, —CH₂(phenyl),            —CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),            —CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl,            and pyridinyl; or        -   (iii) -L₃-T_(14c);    -   each R_(14b) is F, Cl, —OH, —CH₃, or —OCH₃;    -   R_(14c) is adamantanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,        diazepanyl, imidazolyl, indolyl, morpholinyl,        octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, pyrrolyl, triazolyl, or tetrazolyl, each        substituted with zero to 1 substituent selected from F, —OH,        C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —NR_(x)R_(y), —NR_(x)C(O)CH₃,        —C(O)(C₁₋₂ alkyl), —C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂,        —C(O)(tetrahydrofuranyl), —C(O)O(C₁₋₂ alkyl),        —CH₂C(O)NR_(x)R_(y), morpholinyl, methylpiperidinyl, pyrazinyl,        pyridinyl, and pyrrolidinyl;    -   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NR_(x)—,        —C(O)—, —C(O)NR_(x)CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—,        —NR_(x)CH₂—, —NR_(x)CH₂C(O)—, or —O(CH₂)₀₋₂—;    -   R_(v) is H, C₁₋₂ alkyl, or C₁₋₂ fluoroalkyl;    -   each R_(x) is independently H or —CH₃;    -   each R_(y) is independently H or C₁₋₆ alkyl;    -   n is zero, 1, or 2; and    -   p is zero, 1, 2, 3, or 4.

The compounds of Formula (I) or salts thereof in which A is—CR_(x)R₁₂R₁₃; and R₁₂ and R₁₃ together with the carbon atom to whichthey are attached form a cyclic group and the cyclic group has one ormore heteroatoms, the cyclic group is bonded to the indole ring by acarbon atom in the cyclic group.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is:

and A, R₁, R₅, and n are defined in the first aspect or the secondaspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is:

and A, R₁, R₂, R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is

and A, R₁, R_(2a), R_(2b), R_(2c), R_(2d), R₅, n, and p are defined inthe first aspect or the second aspect. Included in this embodiment arecompounds in which R_(2a) is C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄hydroxyalkyl, —(CH₂)₁₋₃OCH₃, C₃₋₆ cycloalkyl, —CH₂C(O)NR_(x)R_(x),—CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl), tetrahydrofuranyl, or phenyl; andeach R_(2b) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆ alkyl,C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₂ alkyl),—(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂ alkyl),—C(O)NR_(x)(C₁₋₃ alkyl), —CR_(x)═CH₂, or —CH═CH(C₃₋₆ cycloalkyl). Alsoincluded in this embodiment are compounds in which R_(2a) is —CH₃; andeach R_(2b) is independently H, Cl, or —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is a 9-membered heterocyclic ring selected from:

and A, R₁, R₂, R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is a 10-membered heterocyclic ring selected from:

and A, R₁, R₂, R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein

-   -   A is:    -   (i) —O-L₁-R₆;    -   (ii) —NR₇R₈;    -   (iii) -L₂-C(O)NR₉R₁₀;    -   (iv) —(CR_(x)R_(x))₁₋₂R₁₁, C₁₋₂ aminoalkyl,        —(CR_(x)R_(x))₁₋₂NR_(x)C(O)R₁₁,        —CH₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),        —CH₂NR_(x)(O)OCH₂(piperidinyl), or        —CH₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);    -   (v) —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon        atom to which they are attached form a cyclic group selected        from azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇        cycloalkyl, diazepanyl, azaspiro[3.3]heptanyl,        diazaspiro[4.5]decanonyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,        pyrrolidinyl, and quinuclidinyl, each substituted with zero to 3        R_(12a);    -   (vi) —CR_(x)═CR_(x)(piperidinyl); or    -   (vii) an aromatic group selected from        [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,        imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl,        phenyl, pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl,        pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl,        quinolinyl, quinoxalinyl,        tetrahydro[1,2,4]triazolo[1,5-a]pyrazinyl,        tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,        tetrahydrothiazolo[5,4-c]pyridinyl,        tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,        thiooxadiazolyl, and triazolyl, each substituted with zero to 2        R_(14a) and zero to 3 R_(14b);    -   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —CH₂C(O)—,        —CH₂C(O)NR_(x)(CR_(x)R_(x))₀₋₂—, —CH₂NR_(x)C(O)—, or        —CH₂NR_(x)C(O)CH₂—;    -   L₂ is a bond or —(CR_(x)R_(x))₁₋₂—;    -   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂        hydroxyalkyl, or —C(O)O(C₁₋₂ alkyl);    -   each R₂ is independently F, Cl, —CN, —OH, C₁₋₃ alkyl, C₁₋₂        fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₂        aminoalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,        —NR_(x)R_(x), —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₀₋₂S(O)₂(C₁₋₃        alkyl), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl), or phenyl;    -   R_(2a) is C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,        —(CH₂)₁₋₃OCH₃, C₃₋₆ cycloalkyl, —CH₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆        cycloalkyl), —CH₂(phenyl), tetrahydrofuranyl, or phenyl;    -   each R_(2b) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆        alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₂        alkyl), —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃(cyclopropyl),        —C(O)O(C₁₋₂ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl), —CR_(x)═CH₂, or        —CH═CH(C₃₋₆ cycloalkyl);    -   each R₅ is independently F, Cl, —CN, C₁₋₂ alkyl, or —OCH₃;    -   R₆ is:        -   (i) C₁₋₂ alkyl, —CH₂C(O)NHCH₂CR_(x)R_(x)OH,            —CH₂C(O)NHCH₂CH₂CR_(x)R_(x)OH, —CH₂C(O)NHCH₂CH₂NR_(x)R_(x),            or —CH₂C(O)NHCH₂CHFCR_(x)R_(x)OH; or        -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,            azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,            diazaspiro[3.5]nonanyl, morpholinyl, tetrahydropyranyl,            octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,            pyrrolidinyl, or quinuclidinyl, each substituted with zero            to 3 R_(6a);    -   each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x),        —N(C₂₋₃ alkyl)₂, —(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂        alkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,        tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,        isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);    -   R₇ is:        -   (i) R_(7a), —CH₂R_(7a), —(CH₂)₁₋₂NR_(x)R_(x),            —(CH₂)₁₋₂NR_(x)C(O)CH₂NR_(x)R_(x), —C(O)R_(7a),            —C(O)CH(NH₂)R_(7a), —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄            alkyl), —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂,            or —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or        -   (ii) C₃₋₆ cycloalkyl substituted with one substituent            selected from —NR_(x)(CH₂)₂₋₃NR_(x)R_(x), —NH(CH₂)₂₋₃NHCH₃,            —NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl),            dimethylamino piperidinyl, and piperazinyl substituted with            a substituent selected from C₁₋₄ alkyl, —C(O)CH₃,            —(CH₂)₁₋₂OCH₃, —CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl),            C₃₋₆ cycloalkyl, pyridinyl, and methylpiperidinyl;    -   R_(7b) is:        -   (i) —OH, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl,            C₁₋₂ aminoalkyl, —(CH₂)₂₋₃C≡CH, —(CR_(x)R_(x))₁₋₂O(C₁₋₂            alkyl), —(CH₂)₁₋₃S(O)₂(C₁₋₂ alkyl), —(CH₂)₀₋₃NR_(x)R_(y),            —(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(y)R_(y), —NR_(x)(C₁₋₄            hydroxyalkyl), —NR_(y)(C₁₋₂ cyanoalkyl), —N(C₁₋₂            cyanoalkyl)₂, —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄            hydroxyfluoroalkyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),            —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),            —N((CH₂)₁₋₂C(O)NR_(x)R_(x))₂, —NR_(x)(CH₂)₁₋₂S(O)₂(C₁₋₂            alkyl), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),            —NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),            —NR_(x)(CH₂CH₂S(O)₂CH₃),            —(CH₂)₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),            —O(CH₂)₁₋₃NR_(x)R_(x), —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y),            —C(O)(CR_(x)R_(x))₁₋₂NR_(y)(C₁₋₄ hydroxyalkyl),            —C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃),            —S(O)₂CH₂CH₂N(CH₃)₂, —(CH₂)₁₋₂R_(7d), —NR_(x)R_(7d),            —NR_(x)(CH₂)₁₋₂R_(7d)), —NR_(7d)R_(7d), —N((CH₂)₁₋₂R_(7d))₂,            —OR_(7d), —C(O)R_(7d), —C(O)(CR_(x)R_(x))₁₋₂R_(7d), or            —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(7d); or        -   (ii) azepanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,            dioxotetrahydrothiopyranyl, dioxothiomorpholinyl,            morpholinyl, oxaazaspiro[3.3]heptanyl,            oxaazaspiro[4.3]octanyl, oxetanyl, piperazinonyl,            piperazinyl, piperidinyl, pyridinyl, pyrimidinyl,            pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydroisoquinolinyl, tetrahydropyranyl, or thiadiazolyl,            each substituted with zero to 1 R_(8a) and zero to 3 R_(8b);    -   each R_(7c) is independently F, —CH₃ or —CH₂CN;    -   R_(7d) is azaspiro[3.5]nonanyl, azetidinyl,        bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,        dioxothiaazaspiro[3.3]heptanyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,        oxaazaspiro[4.4]nonyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,        pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,        thiadiazolyl, or triazolyl, each substituted with zero to 2        substituents independently selected from F, —OH, C₁₋₃ alkyl,        C₁₋₂ hydroxyalkyl, C₁₋₂ alkoxy, —NR_(x)R_(x), —C(O)CH₃,        —S(O)₂CH₃, methylpiperidinyl, methylpyrrolidinyl,        tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and        —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;    -   R₈ is H or C₁₋₂ alkyl;    -   or R₇ and R₈ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidinyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl,        diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.1]octanyl,        azaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl,        diazaspiro[3.3]heptanyl, diazepanonyl, diazepanyl,        diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, imidazolyl,        imidazolidinonyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl,        oxadiazabicyclo[3.3.1]nonanyl, piperazinyl, piperazinonyl,        piperidinyl, pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein        said heterocyclic ring is substituted with zero to 1 R_(7b) and        zero to 2 R_(7c);    -   R_(8a) is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂        alkyl), C₁₋₂ alkoxy, —C(O)(C₁₋₂ alkyl), —C(O)O(C₁₋₂ alkyl),        —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methyl phenyl),        —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),        —(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl,        methylpiperidinyl, or pyridinyl;    -   each R_(8b) is independently F or —CH₃;    -   R₉ is C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, C₂₋₅        hydroxy fluoroalkyl, C₁₋₂ aminoalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),        —(CH₂)₁₋₃N(CH₃)₂, —(CH₂)₁₋₂C(O)NH₂, —(CH₂)₁₋₂S(O)₂OH,        —(CH₂)₁₋₂CR_(x)R_(x)NHS(O)₂CH₃, or —(CH₂)₀₋₃R_(9a);    -   R_(9a) is C₅₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,        piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,        thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted        with zero to 2 substituents independently selected from —OH,        C₁₋₃ alkyl, —NR_(x)R_(x), oxetanyl, phenyl, piperazinyl,        piperidinyl, and pyrrolidinyl;    -   R₁₀ is H, C₁₋₃ alkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), or C₃₋₆        cycloalkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from        azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,        diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,        diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,        indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,        piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each        substituted with zero to 3 R_(10a);    -   each R_(10a) is independently C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl,        —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x),        —CH₂C(O)NR_(x)R_(x), —CH₂(methyltriazolyl), —CH₂CH₂(phenyl),        —CH₂CH₂(morpholinyl), —C(O)(C₁₋₂ alkyl), —C(O)NH₂, —C(O)N(C₁₋₂        alkyl)₂, —C(O)CH₂NR_(x)R_(x), —NR_(x)R_(x), —NHC(O)(C₁₋₂ alkyl),        —C(O)(furanyl), —O(piperidinyl),        —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,        piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,        isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,        pyrimidinyl, or dihydrobenzo[d]imidazolonyl;    -   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,        hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,        piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with        zero to 3 substituents independently selected from F, Cl, —CN,        C₁₋₃ alkyl, C₁₋₂ aminoalkyl, —CH₂(methyloxetanyl),        —CH₂(triazolyl), —CH₂(phenyl), —C(O)CH₂NR_(x)R_(x),        —CH₂CR_(x)R_(x)OH, —CH₂C(O)NR_(x)R_(x), —CH₂CH₂S(O)₂(C₁₋₃        alkyl), —CH₂CH₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl,        and tetrahydropyranyl;    -   each R_(12a) is independently —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl,        C₁₋₂ cyanoalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),        —CH₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),        —(CH₂)₁₋₂NHS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₂ alkoxy,        —NR_(y)R_(y), —NR_(x)(C₁₋₃ fluoroalkyl),        —NR_(x)(CH₂CR_(x)R_(x))OCH₃), —NR_(x)(C₁₋₂ cyanoalkyl),        —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),        —NR_(x)(CH₂C(O)NH₂), —NR_(x)(OCH₃), —NR_(x)CH₂CH₂S(O)₂(C₁₋₂        alkyl), —NR_(x)(CH₂CR_(x)R_(x))OCH₃), —NR_(x)C(O)CH₃,        —NR_(x)C(O)(C₁₋₄ fluoroalkyl), —NR_(x)(O)CR_(x)R_(x)NR_(x)R_(x),        —NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄        hydroxyalkyl), —NR_(x)CH₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂CH₃,        —C(O)(C₁₋₅ alkyl), —C(O)CH₂O(C₁₋₂ alkyl), —C(O)CH₂CH₂O(C₁₋₂        alkyl), —C(O)(CH₂)₁₋₂NR_(x)R_(x), —C(O)CHR_(x)NR_(y)R_(y),        R_(12b), —CR_(x)R_(x)R_(12b), —C(O)R_(12b),        —C(O)CH₂NR_(x)R_(12b), —C(O)NR_(x)R_(12b),        —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),        —NR_(x)CR_(x)R_(x)R_(12b), —N(CH₂CN)R_(12b),        —NR_(x)C(O)CH₂NR_(x)R_(12b), —NR_(x)C(O)CH₂NR_(x)CH₂R_(12b),        —NR_(x)CH₂C(O)NR_(x)R_(12b), or —OR_(12b); or two R_(12a) and        the carbon atom to which they are attached form C═O;    -   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,        diazabicyclo[2.2.1]heptanyl, dioxolanyl,        dioxothiaazaspiro[3.3]heptanyl, dioxidotetrahydrothiopyranyl,        dioxidothiomorpholinyl, imidazolyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,        oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,        oxaazaspiro[4.4]nonanyl, oxetanyl, phenyl, piperazinyl,        piperazinonyl, piperidinyl, pyridinyl, pyrrolidinyl,        quinuclidinyl, tetrahydropyranyl, tetrahydropyranyl, or        triazolyl, each substituted with zero to 4 substituents        independently selected from F, Cl, —OH, C₁₋₃ alkyl, C₁₋₂        hydroxyalkyl, C₁₋₂ alkoxy, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —NR_(x)R_(x),        —C(O)NR_(x)R_(x), —S(O)₂(C₁₋₂ alkyl), and —CH₂S(O)₂(C₁₋₂ alkyl);    -   each R_(14a) is independently:        -   (i) H, F, Cl, —OH, C₁₋₅ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂            hydroxyalkyl, —(CH₂)₀₋₂OCH₃, —CHR_(x)NR_(x) (C₁₋₅ alkyl),            —CHR_(x)NR_(x)(C₁₋₂ cyanoalkyl),            —CHR_(x)NR_(x)((CH₂)₁₋₅OCH₃), —CHR_(x)N((CH₂)₁₋₂OCH₃)₂,            —CH₂NR_(x)(CH₂CCR_(x)), —CH₂NR_(x)CH₂CH₂NR_(x)R_(x),            —(CH₂)₁₋₃CR_(x)R_(x)NR_(x)R_(x),            —CH(NH₂)(CH₂)₃₋₄NR_(x)R_(x), —CH₂NR_(x)(CH₂)₁₋₂O(C₁₋₃            alkyl), —CH₂NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH,            —CH₂NH(CH₂)₁₋₂S(O)₂OH, —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y),            —NR_(x)(CH₂)₂₋₃NR_(x)R_(x), —NR_(x)C(O)(C₁₋₂ alkyl),            —NR_(x)C(O)(C₁₋₂ fluoroalkyl), —NR_(x)C(O)O(C₁₋₃ alkyl),            —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),            —NR_(x)CH₂C(O)CH₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),            —C(O)CH₂CR_(x)R_(x)OH, —C(O)CH₂NR_(x)R_(x),            —C(O)NR_(x)R_(x), —C(O)NR_(x)(CH₂CN),            —C(O)NR_(x)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),            —C(O)N(CH₂CH₃)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),            —C(O)NR_(x)CH₂C(O)NR_(x)R_(x),            —C(O)NR_(x)CH₂CH₂NR_(x)C(O)CH₃,            —O(CR_(x)R_(x))₂₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or            —C(O)CH₂S(O)₂(C₁₋₂ alkyl);        -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,            azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl,            cyclohexyl, diazepanyl, morpholinyl, phenyl, piperazinyl,            piperidinyl, pyrazolyl, pyridinyl, pyrrolidinonyl,            quinolinyl, quinuclidinyl, tetrahydroisoquinolinyl,            tetrahydropyridinyl, or thiazolidinyl, each substituted with            zero to 2 substituents independently selected from C₁₋₄            alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —NR_(x)R_(x),            —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),            —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl),            —CH₂C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, —CH₂(phenyl),            —CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),            —CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl,            and pyridinyl; or        -   (iii) -L₃-R_(14c);    -   each R_(14b) is F, —CH₃, or —OCH₃;    -   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NH—, —C(O)—,        —C(O)NR_(x)(CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—, —NR_(x)CH₂—,        —NR_(x)CH₂C(O)—, —O—, or —O(CH₂)₁₋₂—; and    -   R_(14c) is adamantanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,        imidazolyl, indolyl, morpholinyl,        octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, or tetrazolyl, each substituted with zero to 1        substituent selected from F, —OH, C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl,        —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl),        —C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl),        —C(O)O(C₁₋₂ alkyl), —CH₂C(O)NR_(x)R_(y), morpholinyl,        methylpiperidinyl, pyrazinyl, pyridinyl, and pyrrolidinyl;    -   and G, n, and p is defined in the first aspect or the second        aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein:

-   -   A is:    -   (i) —O-L₁-R₆;    -   (ii) —NR₇R₈;    -   (iii) -L₂-C(O)NR₉R₁₀;    -   (iv) —CHR_(x)R₁₁, —CH₂CH₂R₁₁, —CH₂NH₂, —CH₂NHC(O)R₁₁,        —CH₂NHC(O)CH₂CH₂(piperidinyl), —CH₂NHC(O)OCH₂(piperidinyl), or        —CH₂NHC(O)CH₂CH₂N(CH₃)₂;    -   (v) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom        to which they are attached form a cyclic group selected from        azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₆ cycloalkyl,        azaspiro[3.3]heptanyl, diazaspiro[4.5]decanonyl; morpholinyl,        octahydrocyclopenta[c]pyrrolyl, piperidinyl, pyrrolidinyl, and        quinuclidinyl, each substituted with zero to 3 R_(12a);    -   (vi) —CH═CH(piperidinyl); or    -   (vii) an aromatic group selected from        [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,        imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl,        phenyl, pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl,        pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl,        quinolinyl, quinoxalinyl,        tetrahydro[1,2,4]triazolo[1,5-a]pyrazinyl,        tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,        tetrahydrothiazolo[5,4-c]pyridinyl,        tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,        thiooxadiazolyl, and triazolyl, each substituted with zero to 2        R_(14a) and zero to 3 R_(14b);    -   L₁ is bond, —CH₂—, —CH₂CH₂—, —CH₂C(O)—, —CH₂C(O)NH—,        —CH₂C(O)N(CH₃)—, —CH₂C(O)NHCH₂—, or —CH₂C(O)NHCH₂CH₂—;    -   L₂ is a bond, —CH(CH₃)—, —C(CH₃)₂—, or —CH₂CH₂—;    -   each R₅ is independently F, Cl, —CN, C₁₋₂ alkyl, or —OCH₃;    -   R₆ is:        -   (i) —CH₃, —CH₂C(O)NHCH₂C(CH₃)₂OH, —CH₂C(O)NHCH₂CH₂C(CH₃)₂OH,            —CH₂C(O)NHCH₂CH₂NH₂, or —CH₂C(O)NHCH₂CHFC(CH₃)₂OH; or        -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,            azetidinyl, cyclohexyl, diazabicyclo[2.2.1]heptanyl,            diazaspiro[3.5]nonanyl, morpholinyl,            octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,            pyrrolidinyl, or quinuclidinyl, each substituted with zero            to 2 R_(6a);    -   each R_(6a) is independently F, —OH, —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂,        —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂CH₂OH,        —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —NH₂, —N(CH₃)₂,        —N(CH₂CH₂CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂S(O)₂CH₃,        —CH₂C(O)N(CH₃)₂, —C(O)CH₂N(CH₃)₂, oxetanyl, tetrahydropyranyl,        piperidinyl, isobutylpiperidinyl, or —O(piperidinyl);    -   R₇ is:        -   (i) —CH₂CH₂NH₂, —CH₂CH₂NHC(O)CH₂N(CH₃)₂, —CH₂(isopropyl            azaspiro[3.5]nonanyl), —CH₂(methylpyrrolidinyl),            —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)CH₂CH₂CH₃,            —C(O)CH(NH₂)CH₂CH(CH₃)₂, —C(O)CH(NH₂)CH(CH₃)CH₂CH₃,            —C(O)CH(NH₂)CH₂CH₂C(O)OH, —C(O)CH(NH₂)(CH₂)₃₋₄NH₂,            —C(O)CH(NH₂)(CH₂)₁₋₂C(O)NH₂, —C(O)CH(NH₂)(cyclohexyl),            —C(O)CH(NH₂)(phenyl), —C(O)(aminocyclohexyl),            —C(O)(morpholinyl), —C(O)(pyrrolidinyl),            pentamethylpiperidinyl, methylpiperidinyl-piperidinyl,            methylpyrrolidinyl-pyrrolidinyl, or phenyl substituted with            —OCH₂CH₂(pyrrolidinyl) or —OCH₂CH₂NHCH₂CH₃; or        -   (ii) cyclohexyl substituted with —NR_(x)(CH₂)₂₋₃N(CH₃)₂,            —NHCH₂CH₂NHCH₃, —NH(methylpiperidinyl),            —NH(CH₂)₂₋₃(morpholinyl), dimethylamino piperidinyl, or            piperazinyl substituted with —CH₃, —CH₂CH₃, —C(CH₃)₃,            —CH₂CH(CH₃)₂, —C(O)CH₃, —CH₂CH₂OCH₃, —CH₂(methylphenyl),            —(CH₂)₂₋₃(pyrrolidinyl), cyclopentyl, pyridinyl, or            methylpiperidinyl;    -   R_(7b) is:        -   (i) —OH, C₁₋₆ alkyl, C₃₋₄ fluoroalkyl, C₃₋₄ hydroxyalkyl,            —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂C≡CH, —(CR_(x)R_(x))₁₋₂OCH₃,            —(CH₂)₂₋₃S(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x),            —(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(y)R_(y), —NR_(x)(C₁₋₄            hydroxyalkyl), —NH(CH₂CH₂OCH₃), —NR_(y)(C₁₋₂ cyanoalkyl),            —N(CH₂CH₂CN)₂, —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄            hydroxyfluoroalkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x),            —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),            —N((CH₂)₁₋₂C(O)NR_(x)R_(x))₂, —NR_(x)(CH₂)₁₋₂S(O)₂(C₁₋₂            alkyl), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂CH₂N(CH₃)₂,            —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —NR_(x)(CH₂CH₂S(O)₂CH₃),            —OCH₂CH₂N(CH₃)₂, —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y),            —C(O)(CR_(x)R_(x))₁₋₂NR_(y)(C₁₋₄ hydroxyalkyl),            —C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃),            —S(O)₂CH₂CH₂N(CH₃)₂, —(CH₂)₁₋₂R_(7d), —NR_(x)R_(7d),            —NR_(x)(CH₂)₁₋₂R_(7d)), —NR_(7d)R_(7d), —N((CH₂)₁₋₂R_(7d))₂,            —OR_(7d), —C(O)R_(7d), —C(O)(CR_(x)R_(x))₁₋₂R_(7d), or            —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(7d); or        -   (ii) azepanyl, azetidinyl, cyclobutyl, cyclohexyl,            diazepanyl, dioxotetrahydrothiopyranyl,            dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl,            oxaazaspiro[4.3]octanyl, oxetanyl, piperazinonyl,            piperazinyl, piperidinyl, pyridinyl, pyrimidinyl,            pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydroisoquinolinyl, tetrahydropyranyl, or thiadiazolyl,            each substituted with zero to 1 R_(8a) and zero to 3 R_(8b);    -   each R_(7c) is independently —CH₃ or —CH₂CN;    -   R_(7d) is azaspiro[3.5]nonanyl, azetidinyl,        bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,        dioxothiaazaspiro[3.3]heptanyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,        oxaazaspiro[4.4]nonyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,        pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,        thiadiazolyl, or triazolyl, each substituted with zero to 2        substituents selected from F, —OH, C₁₋₃ alkyl, —CH₂OH, —OCH₃,        —NR_(x)R_(x), —C(O)CH₃, —S(O)₂CH₃, methylpiperidinyl,        methylpyrrolidinyl, tetramethylpiperidinyl,        —OCH₂CH₂(pyrrolidinyl), and —OCH₂CH₂NHCH₂CH₃; and zero to 4        substituents selected from —CH₃;    -   R₈ is H, —CH₃ or —CH₂CH₃;    -   or R₇ and R₈ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidinyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl,        diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.1]octanyl,        azaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl,        diazaspiro[3.3]heptanyl, diazepanonyl, diazepanyl,        diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl,        imidazolidinonyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl,        oxadiazabicyclo[3.3.1]nonanyl, piperazinyl, piperazinonyl,        piperidinyl, pyrrolidinonyl, and pyrrolidinyl, wherein said        heterocyclic ring is substituted with zero to 1 R_(7b) and zero        to 2 R_(7c);    -   R_(8a) is —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂,        —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —OCH₃, —C(O)CH₃, —C(O)OCH₃,        —CH₂(cyclopropyl), —CH₂(methyl phenyl), —(CH₂)₂₋₃(pyrrolidinyl),        —CH₂(methylpyrazolyl), —CH₂(thiophenyl), —NR_(x)R_(x),        cyclopentyl, methylpiperidinyl, or pyridinyl;    -   R_(8a) is —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂,        —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —OCH₃, —C(O)CH₃, —C(O)OCH₃,        —CH₂(cyclopropyl), —CH₂(methyl phenyl), —(CH₂)₂₋₃(pyrrolidinyl),        —CH₂(methylpyrazolyl), —CH₂(thiophenyl), —NR_(x)R_(x),        cyclopentyl, methylpiperidinyl, or pyridinyl;    -   each R_(8b) is —CH₃;    -   R₉ is —CH₃, —CH₂CH₂CF₃, —CH₂CH₂OH, —CH₂C(CH₃)₂OH,        —CH₂C(CH₃)₂CH₂OH, —CH₂CHFC(CH₃)₂OH, —CH₂CH₂C(CH₃)₂OH,        —CH(CH₂OH)₂, —CH₂CH₂OCH₃, —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂,        —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂C(O)NH₂, —CH₂S(O)₂OH,        —CH₂CH₂C(CH₃)₂NHS(O)₂CH₃, or —(CH₂)₀₋₃R_(9a);    -   R_(9a) a is cyclohexyl, cycloheptyl, furanyl, phenyl,        piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl,        quinuclidinyl, thiazolyl, or octahydrocyclopenta[c]pyrrolyl,        each substituted with zero to 2 substituents independently        selected from —OH, C₁₋₃ alkyl, —NH₂, —N(CH₃)₂, oxetanyl, phenyl,        piperazinyl, piperidinyl, and pyrrolidinyl;    -   R₁₀ is H, —CH₃, —CH₂CH₃, —CH₂CH₂OCH₃, or cyclopropyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from        azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,        diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,        diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,        diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,        indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,        piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each        substituted with zero to 2 R_(10a);    -   each R_(10a) is independently —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂OH,        —CH₂CH₂OH, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂CH₂NH₂,        —CH₂CH₂NH(CH₃), —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂,        —CH₂(methyltriazolyl), —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl),        —C(O)CH₃, —C(O)NH₂, —C(O)N(CH₂CH₃)₂, —C(O)CH₂NH(CH₃),        —C(O)CH₂N(CH₃)₂, —NH₂, —N(CH₃)₂, —NHC(O)CH₃, —C(O)(furanyl),        —O(piperidinyl), —C(O)CH₂(diethylcarbamoylpiperidinyl),        methylpiperazinyl, piperidinyl, methylpiperidinyl,        diethylcarbamoylpiperidinyl, isopropylpiperidinyl, pyridinyl,        trifluoromethylpyridinyl, pyrimidinyl, or dihydrobenzo[d]        imidazolonyl;    -   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,        hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,        piperidinyl, or pyrrolidinyl, each substituted with zero to 2        substituents independently selected from F, —CH₃, —CH(CH₃)₂,        —CH₂CN, —CH₂(methyloxetanyl), —CH₂(triazolyl), —CH₂(phenyl),        —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH, —CH₂C(O)N(CH₃)₂,        —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)CH₃, oxetanyl, and        tetrahydropyranyl;    -   each R_(12a) is independently —OH, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,        —CH₂CH(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CN,        —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂,        —CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃, —CH₂CH₂NHS(O)₂CH₃,        —CH₂NR_(x)R_(x), —CH₂CH₂NH(CH₃), —OCH₃, —NR_(x)R_(y),        —NR_(x)(C₂₋₄ fluoroalkyl), —NR_(x)(CH₂CR_(x)R_(x)H₂OCH₃),        —NH(CH₂CN), —N(CH₃)CH₂N(CH₃)₂, —NH(CH₂C(CH₃)₂OH),        —NR_(x)(CH₂C(O)NH₂), —N(CH₃)(OCH₃), —NR_(x)CH₂CH₂S(O)₂CH₃,        —NHC(O)CH₃, —NHC(O)CH₂CF₃, —NHC(O)CHR_(x)NH(CH₃),        —NR_(x)C(O)CH₂N(CH₃)₂, —NHC(O)CH₂N(CH₃)(CH₂CH₃),        —NHC(O)CH₂N(CH₂CH₃)₂, —NHC(O)CH₂NH(CH₂C(CH₃)₂OH),        —NHCH₂C(O)NR_(x)(CH₃), —NHS(O)₂CH₃, —C(O)C(CH₃)₃,        —C(O)CH(CH₂CH₃)₂, —C(O)CH₂OCH₃, —C(O)CH₂CH₂OCH₃,        —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)CH₂CH₂N(CH₃)₂,        —C(O)CH(CH₃)NH(CH₃), —C(O)CH₂N(CH₃)(CH₂CH₃), —C(O)CH₂N(CH₂CH₃)₂,        R_(12b), —CH₂R_(12b), —C(O)R_(12b), —C(O)CH₂R_(12b),        —C(O)CH₂NHR_(12b), —C(O)NR_(x)R_(12b), —NR_(x)C(O)CH₂R_(12b),        —NR_(y)R_(12b), —NR_(x)CH₂R_(12b), —N(CH₂CN)R_(12b),        —NHC(O)CH₂NR_(x)R_(12b), —NHC(O)CH₂NR_(x)CH₂R_(12b),        —NHCH₂C(O)NHR_(12b), or —OR_(12b); or two R_(12a) and the carbon        atom to which they are attached form CO═O;    -   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, cyclopropyl,        diazabicyclo[2.2.1]heptanyl, dioxolanyl,        dioxothiaazaspiro[3.3]heptanyl, dioxidotetrahydrothiopyranyl,        dioxidothiomorpholinyl, imidazolyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,        oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,        oxaazaspiro[4.4]nonanyl, oxetanyl, phenyl, piperazinyl,        piperazinonyl, piperidinyl, pyridinyl, pyrrolidinyl,        quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, or        triazolyl, each substituted with zero to 4 substituents        independently selected from F, —OH, —CH₃, —CH(CH₃)₂, —CH₂OH,        —OCH₃, —CH₂CH₂OCH₃, —NR_(x)R_(x), —C(O)NH₂, —C(O)N(CH₃)₂,        —S(O)₂CH₃, and —CH₂S(O)₂CH₃;    -   each R_(14a) is independently:        -   (i) H, F, Cl, —OH, —CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),            —CH₂CH₂CH₂C(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂OH, —OCH₃,            —CH₂CH₂OCH₃, —CHR_(x)NR_(x)(CH₃), —CH₂N(CH₃)(CH(CH₃)₂),            —CH₂NH(CH₂C(CH₃)₃), —CH₂NH(CH₂CN), —CH₂N(CH₃)(CH₂CH₂OCH₃),            —CH₂N(CH₂CH₂OCH₃)₂, —CH₂NR_(x)(CH₂C≡CH),            —CH₂NHCH₂CH₂N(CH₃)₂, —CH₂CH₂NR_(x)(CH₃), —CH₂CR_(x)(CH₃)NH₂,            —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂CH₂NH₂, —CH(NH₂)(CH₂)₃₋₄NH₂,            —CH₂NHCH₂CH₂O(C₁₋₃ alkyl), —CH₂NHCH₂CH₂OCH₂CH₂OH,            —CH₂NHCH₂CH₂S(O)₂OH, —CH₂C(O)NR_(x)(CH₃), —NR_(x)R_(x),            —NH(CH(CH₃)₂), —NHCH₂CH₂NH(CH₃), —NHCH₂CH₂CH₂N(CH₃)₂,            —NHC(O)CH₃, —NHC(O)CF₃, —NHC(O)OC(CH₃)₃, —NHC(O)CH₂N(CH₃)₂,            —NHC(O)CH₂CH₂N(CH₃)₂, —NHCH₂C(O)CH₂NH(CH₃), —C(O)CH₃,            —C(O)CH₂CH(CH₃)OH, —C(O)CH₂NR_(x)(CH₃), —C(O)NR_(x)R_(x),            —C(O)NH(CH₂CN), —C(O)NHCH₂CH₂CH₂NR_(x)R_(x),            —C(O)NHCH₂CH(CH₃)CH₂NH₂, —C(O)NHCH₂C(O)NH₂,            —C(O)N(CH₃)CH₂CH₂CH₂N(CH₃)₂, —C(O)N(CH₂CH₃)CH₂CH₂N(CH₃)₂,            —OCH₂CH₂CH₂N(CH₃)₂, —C(O)NHCH₂CH₂NHC(O)CH₃, —S(O)₂NH₂, or            —C(O)CH₂S(O)₂CH₃;        -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,            azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl,            cyclohexyl, diazepanyl, morpholinyl, phenyl, piperazinyl,            piperidinyl, pyrazolyl, pyridinyl, pyrrolidinonyl,            quinolinyl, quinuclidinyl, tetrahydroisoquinolinyl,            tetrahydropyridinyl, or thiazolidinyl, each substituted with            zero to 2 substituents independently selected from —CH₃,            —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CF₃, —CH₂CH₂CF₃, —CH₂CH₂OH,            —CH₂CH₂CH(CH₃)OH, —NH₂, —CH₂N(CH₃)₂, —CH₂CH₂NH(CH₃),            —C(O)CH₃, —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)O(C(CH₃)₃),            —CH₂C(O)NR_(x)(CH₃), cyclobutyl, cyclopentyl, —CH₂(phenyl),            —CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),            —CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl,            and pyridinyl; or        -   (iii) -L₃-R_(14c);    -   each R_(14b) is —CH₃;    -   L₃ is —(CH₂)₁₋₃—, —CH(CH₃)—, —CH(NH₂)—, —CH₂NH—, —C(O)—,        —C(O)NH(CH₂)₀₋₄—, —C(O)N(CH₃)CH₂CH₂—, —NH—, —NHC(O)—, —NHCH₂—,        —NHCH₂C(O)—, —O—, or —OCH₂CH₂—;    -   R_(14c) is adamantanyl, azetidinyl, cyclopropyl, cyclohexyl,        diazepanyl, imidazolyl, indolyl, morpholinyl,        octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, or tetrazolyl, each substituted with zero to 1        substituent selected from —OH, —CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,        —C(CH₃)₂OH, —NH₂, —N(CH₃)₂, —NH(C(CH₃)₂, —NHC(O)CH₃, —C(O)CH₃,        —C(O)NH₂, —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl),        —C(O)OCH₂CH₃, —CH₂C(O)NH(CH(CH₃)₂, morpholinyl,        methylpiperidinyl, pyrazinyl, pyridinyl, and pyrrolidinyl;    -   n is zero or 1; and    -   p is zero, 1, 2, or 3.

One embodiment provides a compound of Formula (I), or a salt thereof,wherein:

-   -   G is:

-   -   A is:    -   (i) —OR₆ or —(CR_(x)R_(x))₁₋₂—R₆;    -   (ii) —NR₇R₈;    -   (iii) —C(O)NR₉R₁₀;    -   (vi) —CH₂CH₂R₁₁;    -   (v) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom        to which they are attached form a cyclic group selected from        azetidinyl, C₃₋₆ cycloalkyl, morpholinyl, or piperidinyl, each        substituted with zero to 3 R_(12a); or    -   (vi) an aromatic group selected from pyrazolyl substituted with        zero to 1 R_(14a);    -   R₁ is —CH₃ or —CH(CH₃)₂;    -   each R₂ is independently Cl, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,        —CH₂CN, —OCH₃, —CH₂OCH₃, or —CH₂CH₂S(O)₂CH₃;    -   R₆ is:    -   (a) —CH₃; or    -   (b) azetidinyl, cyclohexyl, or piperidinyl, each substituted        with zero to 2 R_(6a);    -   each R_(6a) is independently —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂,        —CH₂C(CH₃)₂OH, —N(CH₃)₂, —N(CH₂CH₂CH₃)₂, —CH₂CH₂S(O)₂CH₃,        —CH₂C(O)N(CH₃)₂, or tetrahydropyranyl;    -   R₇ and R₈ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidinyl,        diazepanyl, diazaspiro[3.5]nonanyl, piperazinonyl, piperazinyl,        piperidinyl, and pyrrolidinyl, wherein said heterocyclic ring is        substituted with zero to 1 R_(7b) and zero to 2 R_(7c);    -   R_(7b) is:        -   (a) —NR_(x)R_(x), C₁₋₆ alkyl, C₂₋₃ fluoroalkyl, C₁₋₄            hydroxyalkyl, C₁₋₂ cyanoalkyl, —CHR_(x)CH₂OCH₃,            —CH₂C(O)NR_(x)R_(x), —CH₂CH₂C(O)NR_(x)R_(x),            —(CH₂)₂₋₃S(O)₂CH₃, —CH₂CH₂NHS(O)₂CH₃, —NR_(x)R_(x),            —N(CH₃)(CH₂CH₃), —N(CH₂CH₃)₂, —NH(CH₂CN), —N(CH₂CN)₂,            —NR_(x)CH₂C(O)N(CH₃)₂, —NR_(x)C(O)CH₂N(CH₃)₂,            —NH(CH₂CH₂S(O)₂CH₃), —N(CH₂C(O)N(CH₃)₂)₂,            —S(O)₂CH₂CH₂N(CH₃)₂, —C(O)CH₂CH₂N(CH₃)₂, —C(O)CH₂N(CH₃)₂,            —C(O)CH₂NH(CH(CH₃)₂), —C(O)CH₂NH(CH₂CH₂OCH₃),            —C(O)CH₂NH(CH₂CH₂OH), —CH₂(cyclopropyl),            —CH₂(methyloxetanyl), —CH₂(tetrahydrofuranyl),            —CH₂(methyltriazolyl), —CH₂CH₂(morpholinyl),            —NR_(x)(cyclobutyl), —NR_(x)(oxetanyl),            —NR_(x)(pyrimidinyl), —NR_(x)(tetrahydropyranyl),            —NHCH₂(methylsulfonylcyclopropyl), —NHCH₂(methyloxetanyl),            —NHCH₂(methoxypyrimidinyl), —(O)CH₂NH(cyclobutyl),            —N(CH₂(dimethoxypyrimidinyl))₂,            —N(CH₂(methoxypyrimidinyl))₂, —N(CH₂(triazolyl))₂,            —N(CH₂(methyltriazolyl))₂, —N(CH₃)CH₂(cyclopropyl),            —N(CH₃)CH₂(methylpyrazolyl), —N(CH₃)CH₂(pyrimidinyl),            —N(CH₃)CH₂(methylpyrimidinyl),            —N(CH₃)CH₂(dimethoxypyrimidinyl),            —N(CH₃)CH₂(methoxypyrimidinyl), —N(CH₃)CH₂(thiadiazolyl),            —N(CH₃)CH₂(methyltriazolyl), —NH(CH₂(methylpyrimidinyl))₂,            —NH(CH₂(thiadiazolyl), —C(O)CH₂(azetidinyl),            —C(O)CH₂(morpholinyl), —C(O)CH₂(hydroxypiperidinyl),            —C(O)CH₂(pyrrolidinyl), or —C(O)CH₂NHCH₂(cyclopropyl); or        -   (b) cyclobutyl, cyclohexyl, dioxothiomorpholinyl, oxetanyl,            piperazinyl, piperidinyl, tetrahydrofuranyl, or            tetrahydropyranyl, each substituted with zero to 1 R_(8a)            and zero to 3 R_(8b);    -   each R_(7c) is independently —CH₃ or —CH₂CN;    -   R_(8a) is —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂,        —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —C(O)CH₃, —C(O)OCH₃, —CH₂(cyclopropyl),        —CH₂(methyl phenyl), —(CH₂)₂₋₃(pyrrolidinyl),        —CH₂(methylpyrazolyl), —CH₂(thiophenyl), —NR_(x)R_(x),        cyclopentyl, methylpiperidinyl, or pyridinyl;    -   each R_(8b) is —CH₃;    -   R₉ is —CH₂CH₂CF₃ or —CH₂CH₂N(CH₃)₂;    -   R₁₀ is H or C₁₋₂ alkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected piperidinyl        substituted with —C(O)CH₃ or —CH(CH₃)₂;    -   R₁₁ is azetidinyl or piperidinyl, each substituted with zero to        1 substituent selected from —CH₂(triazolyl),        —CH₂(methyloxetanyl), —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH,        —CH₂C(O)N(CH₃)₂, —CH₂CH₂S(O)₂CH₃, and oxetanyl;    -   each R_(12a) is independently —OH, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,        —CH₂CH(CH₃)₂, —CH₂CN, —CH₂C(CH₃)₂OH, —CH₂C(O)NH(CH₃),        —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —C(CH₃)₂CH₂C(O)N(CH₃)₂,        —CH₂CH₂S(O)₂CH₃, —NR_(x)R_(y), —NR_(x)(CH₂CHF₂),        —N(R_(x))(CH₂CH₂CF₃), —NR_(x)(CH₂CH₂OCH₃), —NR_(x)(C₁₋₂        cyanoalkyl), —NR_(x)(CH₂CH₂OH), —N(CH₂CH₂OH)(CH₂C(O)N(CH₃)₂),        —N(CH₂CH₂OH)(CH₂CH₂S(O)₂CH₃), —N(CH₂CH₂S(O)₂CH₃)₂,        —NR_(x)(CH₂CH₂OCH₃), —NR_(x)CH₂CR_(x)R_(x)S(O)₂CH₃,        —NR_(x)CH₂CH₂S(O)₂CF₃, —NR_(x)CH₂CH₂S(O)₂NH₂, —NR_(x)C(O)CH₃,        —NR_(x)C(O)CH₂N(CH₃)₂, —NR_(x)(CR_(x)R_(x)C(O)NR_(x)R_(x)),        —NHCH₂C(O)NR_(x)(C(CH₃)₃),        —NR_(x)(CR_(x)R_(x)C(O)CH₂NR_(x)R_(x)),        —NH(CH₂C(O)N(CH₃)CH₂CH₂OCH₃), —N(CH₂CH₃)₂,        —N(CH₂CH₃)(CH₂C(O)N(CH₃)₂), —N(CH₂CH₃)(CH₂CH₂S(O)₂CH₃),        —N(CH₂CN)₂, —N(CH₂CN)(CH₂C(O)N(CH₃)₂),        —N(CH₂CN)(CH₂CH₂S(O)₂CH₃), —N(CH₂C(O)NR_(x)R_(x))₂,        —N(CH₂(methyloxetanyl))₂, —C(O)CH₂N(CH₃)₂, —C(O)CH₂CH₂N(CH₃)₂,        R_(12b), —CH₂R_(12b), —NR_(x)R_(12b), —N(cyclopropyl)R_(12b),        —NR_(x)CHR_(x)R_(12b), —NHC(O)R_(12b),        —NHCR_(x)R_(x)C(O)R_(12b), —N(CH₂CH₃)(CH₂R_(12b)),        —N(CH₂CH₂OH)R_(12b), —N(CH₂CH₂OH)(CH₂R_(12b)), —N(CH₂CN)R_(12b),        —N(CH₂CN)(CH₂R_(12b)), or —N(CH₂(methyloxetanyl))₂; or two        R_(12a) and the carbon atom to which they are attached form C═O;    -   R_(12b) is azaspiro[3.5]nonanyl, azetidinyl, cyclopropyl,        cyclopentyl, dioxotetrahydrothiofuranyl,        dioxidotetrahydrothiopyranyl, dioxothiaazaspiro[3.3]heptanyl,        morpholinyl, oxaazaspiro[3.3]heptanyl, oxazolyl, oxetanyl,        phenyl, piperazinonyl, piperidinyl, pyrazinyl, pyridinyl,        pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl,        tetrahydropyranyl, or triazolyl, each substituted with zero to 4        substituents independently selected from F, —CN, —CH₃,        —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, C₁₋₂ cyanoalkyl,        —OCH₃, —CH₂C(O)NH(CH₃), —C(O)NR_(x)R_(x), —S(O)₂CH₃, —S(O)₂CH₃,        and —CH₂S(O)₂CH₃; and    -   R_(14a) is piperidinyl or —CH₂CH₂(morpholinyl);    -   and R₅ and n are defined in the first aspect or the second        aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein:

-   -   G is:

-   -   A is:    -   (i) —OR₆ or —O(CR_(x)R_(x))₁₋₂—R₆;    -   (ii) —NR₇R₈;    -   (iii) —C(O)NR₉R₁₀;    -   (vi) —CH₂CH₂R₁₁;    -   (v) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom        to which they are attached form a cyclic group selected from        azetidinyl, C₃₋₆ cycloalkyl, morpholinyl, or piperidinyl, each        substituted with zero to 3 R_(12a); or    -   (vi) an aromatic group selected from pyrazolyl substituted with        zero to 1 R_(14a);    -   R₁ is —CH(CH₃)₂;    -   each R₂ is independently Cl, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH,        —OCH₃, —CH₂OCH₃, or —CH₂CH₂S(O)₂CH₃;    -   R₆ is:        -   (a) —CH₃; or        -   (b) azetidinyl, cyclohexyl, or piperidinyl, each substituted            with zero to 2 R_(6a);    -   each R_(6a) is independently —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂,        —CH₂C(CH₃)₂OH, —N(CH₃)₂, —N(CH₂CHCH)₂, —CH₂CH₂S(O)₂CH₃,        —CH₂C(O)N(CH₃)₂, or tetrahydropyranyl;    -   R₇ and R₈ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidinyl,        diazepanyl, diazaspiro[3.5]nonanyl, piperazinonyl, piperazinyl,        piperidinyl, and pyrrolidinyl, wherein said heterocyclic ring is        substituted with zero to 1 R_(7b) and zero to 2 R_(7c);    -   R_(7b) is:        -   (a) —NR_(x)R_(x), C₁₋₆ alkyl, C₂₋₃ fluoroalkyl, C₁₋₄            hydroxyalkyl, C₁₋₂ cyanoalkyl, —CHR_(x)CH₂OCH₃,            —CH₂C(O)NR_(x)R_(x), —CH₂CH₂C(O)NR_(x)R_(x),            —(CH₂)₂₋₃S(O)₂CH₃, —CH₂CH₂NHS(O)₂CH₃, —NR_(x)R_(x),            —N(CH₃)(CH₂CH₃), —N(CH₂CH₃)₂, —NH(CH₂CN), —N(CH₂CN)₂,            —NR_(x)CH₂C(O)N(CH₃)₂, —NR_(x)C(O)CH₂N(CH₃)₂,            —NH(CH₂CH₂S(O)₂CH₃), —N(CH₂C(O)N(CH₃)₂)₂,            —S(O)₂CH₂CH₂N(CH₃)₂, —C(O)CH₂CH₂N(CH₃)₂, —C(O)CH₂N(CH₃)₂,            —C(O)CH₂NH(CH(CH₃)₂), —C(O)CH₂NH(CH₂CH₂OCH₃),            —C(O)CH₂NH(CH₂CH₂OH), —CH₂(cyclopropyl),            —CH₂(methyloxetanyl), —CH₂(tetrahydrofuranyl),            —CH₂(methyltriazolyl), —CH₂CH₂(morpholinyl),            —NR_(x)(cyclobutyl), —NR_(x)(oxetanyl),            —NR_(x)(pyrimidinyl), —NR_(x)(tetrahydropyranyl),            —NHCH₂(methylsulfonylcyclopropyl), —NHCH₂(methyloxetanyl),            —NHCH₂(methoxypyrimidinyl), —C(O)CH₂NH(cyclobutyl),            —N(CH₂(dimethoxypyrimidinyI))₂,            —N(CH₂(methoxypyrimidinyl))₂, —N(CH₂(triazolyl))₂,            —N(CH₂(methyltriazolyl))₂, —N(CH₃)CH₂(cyclopropyl),            —N(CH₃)CH₂(methylpyrazolyl), —N(CH₃)CH₂(pyrimidinyl),            —N(CH₃)CH₂(methylpyrimidinyl),            —N(CH₃)CH₂(dimethoxypyrimidinyl),            —N(CH₃)CH₂(methoxypyrimidinyl), —N(CH₃)CH₂(thiadiazolyl),            —N(CH₃)CH₂(methyltriazolyl), —NH(CH₂(methylpyrimidinyl))₂,            —NH(CH₂(thiadiazolyl), —C(O)CH₂(azetidinyl),            —C(O)CH₂(morpholinyl), —C(O)CH₂(hydroxypiperidinyl),            —C(O)CH₂(pyrrolidinyl), or —C(O)CH₂NHCH₂(cyclopropyl); or        -   (b) cyclobutyl, cyclohexyl, dioxothiomorpholinyl, oxetanyl,            piperazinyl, piperidinyl, tetrahydrofuranyl, or            tetrahydropyranyl, each substituted with zero to 1 R_(8a)            and zero to 3 R_(8b);    -   each R_(7c) is independently —CH₃ or —CH₂CN;    -   R_(8a) is —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂,        —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —C(O)CH₃, —C(O)OCH₃, —CH₂(cyclopropyl),        —CH₂(methyl phenyl), —(CH₂)₂₋₃(pyrrolidinyl),        —CH₂(methylpyrazolyl), —CH₂(thiophenyl), —NR_(x)R_(x),        cyclopentyl, methylpiperidinyl, or pyridinyl;    -   each R_(8b) is —CH₃;    -   R₉ is —CH₂CH₂CF₃ or —CH₂CH₂N(CH₃)₂;    -   R₁₀ is H or Cl₁₋₂ alkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected piperidinyl        substituted with —C(O)CH₃ or —CH(CH₃)₂;    -   R₁₁ is azetidinyl or piperidinyl, each substituted with zero to        1 substituent selected from —CH₂(triazolyl),        —CH₂(methyloxetanyl), —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH,        —CH₂C(O)N(CH₃)₂, —CH₂CH₂S(O)₂CH₃, and oxetanyl;    -   each R_(12a) is independently —OH, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,        —CH₂CH(CH₃)₂, —CH₂CN, —CH₂C(CH₃)₂OH, —CH₂C(O)NH(CH₃),        —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —C(CH₃)₂CH₂C(O)N(CH₃)₂,        —CH₂CH₂S(O)₂CH₃, —NR_(x)R_(y), —NR_(x)(CH₂CHF₂),        —N(R_(x))(CH₂CH₂CF₃), —NR_(x)(CH₂CH₂OCH₃), —NR_(x)(C₁₋₂        cyanoalkyl), —NR_(x)(CH₂CH₂OH), —N(CH₂CH₂OH)(CH₂C(O)N(CH₃)₂),        —N(CH₂CH₂OH)(CH₂CH₂S(O)₂CH₃), —N(CH₂CH₂S(O)₂CH₃)₂,        —NR_(x)(CH₂CH₂OCH₃), —NR_(x)CH₂CR_(x)R_(x)S(O)₂CH₃,        —NR_(x)CH₂CH₂S(O)₂CF₃, —NR_(x)CH₂CH₂S(O)₂NH₂, —NR_(x)C(O)CH₃,        —NR_(x)C(O)CH₂N(CH₃)₂, —NR_(x)(CR_(x)R_(x)C(O)NR_(x)R_(x)),        NHCH₂C(O)NR_(x)(C(CH₃)₃),        —NR_(x)(CR_(x)R_(x)C(O)CH₂NR_(x)R_(x)),        —NH(CH₂C(O)N(CH₃)CH₂CH₂OCH₃), —N(CH₂CH₃)₂,        —N(CH₂CH₃)(CH₂C(O)N(CH₃)₂), —N(CH₂CH₃)(CH₂CH₂S(O)₂CH₃),        —N(CH₂CN)₂, —N(CH₂CN)(CH₂C(O)N(CH₃)₂),        —N(CH₂CN)(CH₂CH₂S(O)₂CH₃), —N(CH₂C(O)NR_(x)R_(x))₂,        —N(CH₂(methyloxetanyl))₂, —C(O)CH₂N(CH₃)₂, —C(O)CH₂CH₂N(CH₃)₂,        R_(12b), —CH₂R_(12b), —NR_(x)R_(12b), —N(cyclopropyl)R_(12b),        —NR_(x)CHR_(x)R_(12b), —NHC(O)R_(12b),        —NHCR_(x)R_(x)C(O)R_(12b), —N(CH₂CH₃)(CH₂R_(12b)),        —N(CH₂CH₂OH)R_(12b), —N(CH₂CH₂OH)(CH₂R_(12b)), —N(CH₂CN)R_(12b),        —N(CH₂CN)(CH₂R_(12b)), or —N(CH₂(methyloxetanyl))₂; or two        R_(12a) and the carbon atom to which they are attached form C═O;    -   R_(12b) is azaspiro[3.5]nonanyl, azetidinyl, cyclopropyl,        cyclopentyl, dioxotetrahydrothiofuranyl,        dioxidotetrahydrothiopyranyl, dioxothiaazaspiro[3.3]heptanyl,        morpholinyl, oxaazaspiro[3.3]heptanyl, oxazolyl, oxetanyl,        phenyl, piperazinonyl, piperidinyl, pyrazinyl, pyridinyl,        pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl,        tetrahydropyranyl, or triazolyl, each substituted with zero to 4        substituents independently selected from F, —CN, —CH₃,        —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, C₁₋₂ cyanoalkyl,        —OCH₃, —CH₂C(O)NH(CH₃), —C(O)NR_(x)R_(x), —S(O)₂CH₃, and        —CH₂S(O)₂CH₃;    -   R_(14a) is piperidinyl or —CH₂CH₂(morpholinyl);    -   and G, n, R₅, and p are defined in the first aspect or the        second aspect

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is:

A is —NR₇R₈; and R₁, R₂, R₅, n, and p are defined in the first aspect orthe second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is:

R₁ is —CH(CH₃)₂; A is piperazinyl; and R₁, R₂, R₅, n, and p are definedin the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is

A is —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom towhich they are attached form a cyclic group selected from azetidinyl,C₄₋₆ cycloalkyl, or piperidinyl, each substituted with zero to 4R_(12a); and R₁, R₂, R_(2a), R_(2b), R₅, R_(12a), n, and p are definedin the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is

A is —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom towhich they are attached form a cyclic group selected from cyclopentyland cyclohexyl, each substituted with zero to 1 R_(12a); R₁ is—CH(CH₃)₂; R_(12a) is —NR_(y)R_(y), —NR_(x)(C₁₋₃ fluoroalkyl),—NR_(x)(CH₂CH₂O(C₁₋₃ alkyl)), —NR_(x)(C₁₋₂ cyanoalkyl),—NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),—NR_(x)(CH₂C(O)NR_(x)R_(x)), —CR_(x)R_(x)R_(12b), —NR_(x)R_(12b), or—NR_(x)CR_(x)R_(x)R_(12b); R_(12b) is cyclopropyl, cyclopentyl,dioxotetrahydrothiofuranyl, dioxidotetrahydrothiopyranyl, morpholinyl,oxaazaspiro[3.3]heptanyl, oxazolyl, oxetanyl, phenyl, piperidinyl,pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydropyranyl, or triazolyl, each substitutedwith zero to 4 substituents independently selected from F, —CN, —CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, C₁₋₂ cyanoalkyl, —OCH₃,—CH₂C(O)NH(CH₃), —C(O)NR_(x)R_(x), —S(O)₂CH₃, and —CH₂S(O)₂CH₃; and R₂,R₅, n, and p are defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂hydroxyalkyl, or —C(O)O(C₁₋₂ alkyl); and G, A, R₅, and n are defined inthe first aspect or the second aspect. Included in this embodiment arecompounds in which R₁ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CHF₂, or —CH₂CF₃.Also included in this embodiment are compounds in which R₁ is —CH₃ or—CH(CH₃)₂. Additionally, included in this embodiment are compounds inwhich R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein each R₂ is independently F, Cl, —CN, —OH, C₁₋₃ alkyl, C₁₋₂fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₂ aminoalkyl,—(CH₂)₀₋₂O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl, —NR_(x)R_(x),—(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl), —CH₂(C₃₋₆cycloalkyl), —CH₂(phenyl), or phenyl; and G, A, R₁, R₅, R_(x), and n aredefined in the first aspect or the second aspect. Included in thisembodiment are compounds in which each R₂ is independently Cl, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —OCH₃, —CH₂OCH₃, or —CH₂CH₂S(O)₂CH₃.Also, included in this embodiment are compounds in which each R₂ isindependently Cl, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —OCH₃, —CH₂OCH₃, or—CH₂CH₂S(O)₂CH₃.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —O-L₁-R₆; and G, R₁, R₅, R₆, R_(x), L₁, and n are definedin the first aspect or the second aspect. Included in this embodimentare compounds in which L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —CH₂C(O)—,—CH₂C(O)NR_(x)(CR_(x)R_(x))₀₋₂—, —CH₂NR_(x)C(O)—, or —CH₂NR_(x)C(O)CH₂—;and each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x), —N(C₂₋₃ alkyl)₂,—(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl,piperazinyl, or —O(piperidinyl). Also included in this embodiment arecompounds in which each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x),—(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl,piperazinyl, or —O(piperidinyl).

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —O-L₁-R₆; L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —CH₂C(O)—,—CH₂C(O)NR_(x)(CR_(x)R_(x))₀₋₂—, —CH₂NR_(x)C(O)—, or —CH₂NR_(x)C(O)CH₂—;R₆ is: (i) C₁₋₂ alkyl, —CH₂C(O)NHCH₂CR_(x)R_(x)OH,—CH₂C(O)NHCH₂CH₂CR_(x)R_(x)OH, —CH₂C(O)NHCH₂CH₂NR_(x)R_(x), or—CH₂C(O)NHCH₂CHFCR_(x)R_(x)OH; or (ii) azabicyclo[3.2.1]octanyl,azaspiro[5.5]undecanyl, azetidinyl, C₃₋₆ cycloalkyl,diazabicyclo[2.2.1]heptanyl, diazaspirop[3.5]nonanyl, morpholinyl,tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl,piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zeroto 3 R_(6a); and each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x), —N(C₂₋₃alkyl)₂, —(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl,piperazinyl, or —O(piperidinyl). Also included in this embodiment arecompounds in which each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x),—(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl,piperazinyl, or —O(piperidinyl); and G, R₁, R₅, R_(x), and n are definedin the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —NR₇R₈; and G, R₁, R₅, R₇, R₈, R_(x), R_(y), n, and p aredefined in the first aspect or the second aspect. Included in thisembodiment are compounds in which R₇ is: (i) —CH₂CH₂NH₂,—CH₂CH₂NHC(O)CH₂N(CH₃)₂, —CH₂(isopropyl azaspiro[3.5]nonanyl),—CH₂(methylpyrrolidinyl), —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)CH₂CH₂CH₃,—C(O)CH(NH₂)CH₂CH(CH₃)₂, —C(O)CH(NH₂)CH(CH₃)CH₂CH₃,—C(O)CH(NH₂)CH₂CH₂C(O)OH, —C(O)CH(NH₂)(CH₂)₃₋₄NH₂,—C(O)CH(NH₂)(CH₂)₁₋₂C(O)NH₂, —C(O)CH(NH₂)(cyclohexyl),—C(O)CH(NH₂)(phenyl), —C(O)(aminocyclohexyl), —C(O)(morpholinyl),—C(O)(pyrrolidinyl), pentamethylpiperidinyl,methylpiperidinyl-piperidinyl, methylpyrrolidinyl-pyrrolidinyl, orphenyl substituted with —OCH₂CH₂(pyrrolidinyl) or —OCH₂CH₂NHCH₂CH₃; or(ii) cyclohexyl substituted with —NR_(x)(CH₂)₂₋₃N(CH₃)₂, —NHCH₂CH₂NHCH₃,—NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl), dimethylaminopiperidinyl, or piperazinyl substituted with —CH₃, —CH₂CH₃, —C(CH₃)₃,—CH₂CH(CH₃)₂, —C(O)CH₃, —CH₂CH₂OCH₃, —CH₂(methylphenyl),—(CH₂)₂₋₃(pyrrolidinyl), cyclopentyl, pyridinyl, or methylpiperidinyl;R_(7b) is: (i) —OH, C₁₋₆alkyl, C₃₋₄ fluoroalkyl, C₃₋₄ hydroxyalkyl,—CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂C≡CH, —(CR_(x)R_(x))₁₋₂OCH₃,—(CH₂)₂₋₃S(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂C(O)NR_(x)R_(x),—NR_(y)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl), —NH(CH₂CH₂OCH₃), —NR_(y)(C₁₋₂cyanoalkyl), —N(CH₂CH₂CN)₂, —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄hydroxyfluoroalkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x),—NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —N((CH₂)₁₋₂C(O)NR_(x)R_(x))₂,—NR_(x)(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),—NR_(x)CH₂CH₂N(CH₃)₂, —NR_(x)(O)(CH₂)₁₋₂NR_(x)R_(x),—NR_(x)(CH₂CH₂S(O)₂CH₃), —OCH₂CH₂N(CH₃)₂,—C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y), —C(O)(CR_(x)R_(x))₁₋₂NR_(y)(C₁₋₄hydroxyalkyl), —C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃),—S(O)₂CH₂CH₂N(CH₃)₂, —(CH₂)₁₋₂R_(7d), —NR_(x)R_(7d),—NR_(x)(CH₂)₁₋₂R_(7d)), —NR_(7d)R_(7d), —N((CH₂)₁₋₂R_(7d))₂, —OR_(7d),—C(O)R_(7d), —C(O)(CR_(x)R_(x))₁₋₂R_(7d), or—C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(7d); or (ii) azepanyl, azetidinyl,cyclobutyl, cyclohexyl, diazepanyl, dioxotetrahydrothiopyranyl,dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl,oxaazaspiro[4.3]octanyl, oxetanyl, piperazinonyl, piperazinyl,piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, orthiadiazolyl, each substituted with zero to 1 R_(8a) and zero to 3R_(8b); R_(7d) is azaspiro[3.5]nonanyl, azetidinyl,bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl, dioxothiaazaspiro[3.3]heptanyl,morpholinyl, oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,oxaazaspiro[4.4]nonyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,pyrrolidinyl, tetrahydropyranyl, tetrahydropyranyl, thiadiazolyl, ortriazolyl, each substituted with zero to 2 substituents selected from F,—OH, C₁₋₃ alkyl, —CH₂OH, —OCH₃, —NR_(x)R_(x), —C(O)CH₃, —S(O)₂CH₃,methylpiperidinyl, methylpyrrolidinyl, tetramethylpiperidinyl,—OCH₂CH₂(pyrrolidinyl), and —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituentsselected from —CH₃; R₈ is H, —CH₃ or —CH₂CH₃; R_(8a) is —OH, C₁₋₄ alkyl,C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), C₁₋₂ alkoxy, —C(O)(C₁₋₂alkyl), —C(O)O(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methylphenyl), —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),—(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl, methylpiperidinyl,or pyridinyl; and each R_(8b) is independently F or —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —NR₇R₈; and G, R₁, R₅, R₇, R₈, R_(x), and n are defined inthe first aspect or the second aspect. Included in this embodiment arecompounds in which R₇ is: R_(7a), —CH₂R_(7a), —C(O)R_(7a),—C(O)CH(NH₂)R_(7a), —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄ alkyl),—C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or—C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or (ii) C₃₋₆ cycloalkyl substituted withone substituent selected from —NR_(x)(CH₂)₂₋₃NR_(x)R_(x),—NH(CH₂)₂₋₃NHCH₃, —NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl),dimethylamino piperidinyl, and piperazinyl substituted with asubstituent selected from C₁₋₄ alkyl, —C(O)CH₃, —(CH₂)₁₋₂OCH₃,—CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl), C₃₋₆ cycloalkyl, pyridinyl,and methylpiperidinyl; R_(7b) is: (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl,—(CH₂)₂₋₃C≡CH, —(CH₂)₀₋₃NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),—N(CH₃)CH₂CH₂NH₂, —O(CH₂)₁₋₃NR_(x)R_(x), —(CH₂)₁₋₂R_(7d),—NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or (ii) azepanyl, diazepanyl,morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with zero to1 R_(8a) and zero to 3 R_(8b); R_(7d) is azaspiro[3.5]nonanyl, C₃₋₆cycloalkyl, morpholinyl, phenyl, piperidinyl, or pyrrolidinyl, eachsubstituted with zero to 1 substituent selected from C₁₋₃ alkyl, —NH₂,methylpiperidinyl, methylpyrrolidinyl, —OCH₂CH₂(pyrrolidinyl),—OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃; and R₈is H or C₁₋₂ alkyl; R_(8a) is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl,—(CH₂)₁₋₂O(C₁₋₂ alkyl), —C(O)(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl),—(CH₂)₁₋₂(methyl phenyl), —(CH₂)₁₋₃(pyrrolidinyl),—(CH₂)₁₋₂(methylpyrazolyl), —(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆cycloalkyl, methylpiperidinyl, or pyridinyl; and each R_(8b) isindependently F or —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —NR₇R₈; and G, R₁, R₅, R₇, R₈, R_(x), R_(y), and n aredefined in the first aspect or the second aspect. Included in thisembodiment are compounds in which R₇ and R₈ together with the nitrogenatom to which they are attached form a heterocyclic ring selectedazetidinyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl,diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.1]octanyl,azaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl, diazaspiro[3.3]heptanyl,diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,diazaspiro[5.5]undecanyl, imidazolyl, imidazolidinonyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, oxadiazabicyclo[3.3.1]nonanyl,piperazinyl, piperazinonyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl,and pyrrolyl, wherein said heterocyclic ring is substituted with zero to1 R_(7b) and zero to 2 R_(7c); R_(7b) is: (i) —OH, C₁₋₆ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₂ aminoalkyl, —(CH₂)₂₋₃C≡CH,—(CR_(x)R_(x))₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₃S(O)₂(C₁₋₂ alkyl),—(CH₂)₀₋₃NR_(x)R_(y), —(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(y)R_(y),—NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(y)(C₁₋₂ cyanoalkyl), —N(C₁₋₂cyanoalkyl)₂, —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄hydroxyfluoroalyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),—NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —N((CH₂)₁₋₂C(O)NR_(x)R_(x))₂,—NR_(x)(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),—NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),—NR_(x)(CH₂CH₂S(O)₂CH₃), —(CH₂)₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),—O(CH₂)₁₋₃NR_(x)R_(x), —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y),—C(O)(CR_(x)R_(x))₁₋₂NR_(y)(C₁₋₄ hydroxyalkyl),—C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃), —S(O)₂CH₂CH₂N(CH₃)₂,—(CH₂)₁₋₂R_(7d), —NR_(x)R_(7d), —NR_(x)(CH₂)₁₋₂R_(7d)), —NR_(7d)R_(7d),—N((CH₂)₁₋₂R_(7d))₂, —OR_(7d), —C(O)R_(7d), —C(O)(CR_(x)R_(x))₁₋₂R_(7d),or —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(7d); or (ii) azepanyl, azetidinyl, C₃₋₆cycloalkyl, diazepanyl, dioxotetrahydrothiopyranyl,dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl,oxaazaspiro[4.3]octanyl, oxetanyl, piperazinonyl, piperazinyl,piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, orthiadiazolyl, each substituted with zero to 1 R_(8a) and zero to 3R_(8b); each R_(7c) is independently F, —CH₃ or —CH₂CN; R_(7d) isazaspiro[3.5]nonanyl, azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆cycloalkyl, dioxothiaazaspiro[3.3]heptanyl, morpholinyl,oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,oxaazaspiro[4.4]nonyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, ortriazolyl, each substituted with zero to 2 substituents independentlyselected from F, —OH, C₁₋₃ alkyl, C₁₋₂ hydroxyalkyl, C₁₋₂ alkoxy,—NR_(x)R_(x), —C(O)CH₃, —S(O)₂CH₃, methylpiperidinyl,methylpyrrolidinyl, tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and—OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃; R_(8a)is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), C₁₋₂alkoxy, —C(O)(C₁₋₂ alkyl), —C(O)O(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl),—(CH₂)₁₋₂(methyl phenyl), —(CH₂)₁₋₃(pyrrolidinyl),—(CH₂)₁₋₂(methylpyrazolyl), —(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆cycloalkyl, methylpiperidinyl, or pyridinyl; and each R_(8b) isindependently F or —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —NR₇R₈; and G, R₁, R₅, R₇, R₈, and n are defined in thefirst aspect or the second aspect. Included in this embodiment arecompounds in which R₇ and R₈ together with the nitrogen atom to whichthey are attached form a heterocyclic ring selected from azetidinyl,diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,diazaspiro[5.5]undecanyl, imidazolyl, imidazolidinonyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein said heterocyclicring is substituted with zero to 1 R_(7b) and zero to 2 R_(7c); R_(7b)is: (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₂₋₃C≡CH,—(CH₂)₀₋₃NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —N(CH₃)CH₂CH₂NH₂,—O(CH₂)₁₋₃NR_(x)R_(x), —(CH₂)₁₋₂R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or—OR_(7d); or (ii) azepanyl, diazepanyl, morpholinyl, piperazinyl,piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, ortetrahydroisoquinolinyl, each substituted with zero to 1 R_(8a) and zeroto 3 R_(8b); each R_(7c) is independently F, —CH₃ or —CH₂CN; R_(8a) is—OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —C(O)(C₁₋₂alkyl), —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methyl phenyl),—(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),—(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl, methylpiperidinyl,or pyridinyl; and each R_(8b) is independently F or —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —(CR_(x)R_(x))₁₋₃R₁₁, —(CR_(x)R_(x))₁₋₃NR_(x)C(O)R₁₁, or—(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x); and G, R₁, R₅, R₁₁,R_(x), and n are defined in the first aspect or the second aspect.Included in this embodiment are compounds in which R₁₁ is azetidinyl,azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl, piperidinyl,pyridinyl, or pyrrolidinyl, each substituted with zero to 3 substituentsindependently selected from F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂ aminoalkyl,—CH₂(methyloxetanyl), —CH₂(triazolyl), —CH₂(phenyl),—C(O)CH₂NR_(x)R_(x), —CH₂CR_(x)R_(x)OH, —CH₂C(O)NR_(x)R_(x),—CH₂CH₂S(O)₂(C₁₋₃ alkyl), —CH₂CH₂S(O)(C₁₋₃ alkyl), oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl. Also included in thisembodiment are compounds in which Rut is azetidinyl,azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl, piperidinyl,pyridinyl, or pyrrolidinyl, each substituted with zero to 3 substituentsindependently selected from F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂ aminoalkyl,—CH₂(phenyl), —C(O)CH₂NR_(x)R_(x), —CH₂CR_(x)R_(x)OH,—CH₂C(O)NR_(x)R_(x), —CH₂CH₂S(O)₂(C₁₋₃ alkyl), —CH₂CH₂S(O)(C₁₋₃ alkyl),oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbonatom to which they are attached form a cyclic group selected fromazabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,diazepanyl, azaspiro[3.3]heptanyl, diazaspiro[4.5]decanonyl,morpholinyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,pyrrolidinyl, and quinuclidinyl, each substituted with zero to 4R_(12a), and G, R₁, R₅, R₁₂, R₁₃, R_(x), R_(y), and n are defined in thefirst aspect or the second aspect. Included in this embodiment arecompounds in which R₁₂ and R₁₃ together with the carbon atom to whichthey are attached form a cyclic group selected fromazabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl,and quinuclidinyl, each substituted with zero to 4 R_(12a). Alsoincluded in this embodiment are compounds in which each R_(12a) isindependently —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₄hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —CH₂C(O)NR_(x)R_(x),—(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NHS(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂NR_(x)R_(x), C₁₋₂ alkoxy, —NR_(y)R_(y), —NR_(x)(C₁₋₃fluoroalkyl), —NR_(x)(CH₂CH₂O(C₁₋₂ alkyl)), —NR_(x)(C₁₋₂ cyanoalkyl),—NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(x)(CH₂C(O)NH₂),—NR_(x)(OCH₃), —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl), —NR_(x)C(O)CH₃,—NR_(x)C(O)(C₁₋₂ fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),—NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄ hydroxyalkyl),—NR_(x)CH₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂CH₃, —C(O)(C₁₋₅alkyl),—C(O)CH₂O(C₁₋₂ alkyl), —C(O)CH₂CH₂O(C₁₋₂ alkyl),—C(O)(CH₂)₁₋₂NR_(x)R_(x), —C(O)CHR_(x)NR_(y)R_(y), R_(12b),—CR_(x)R_(x)R_(12b), —C(O)R_(12b), —C(O)CH₂NR_(x)R_(12b),—C(O)NR_(x)R_(12b), —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),—NR_(x)CR_(x)R_(x)R_(12b), —NR_(x)C(O)CH₂NR_(x)R_(12b),—NR_(x)C(O)CH₂NR_(x)CH₂R_(12b), —NR_(x)CH₂C(O)NR_(x)R_(12b), or—OR_(12b); and R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆cycloalkyl, diazabicyclo[2.2.1]heptanyl, dioxolanyl,dioxothiaazaspiro[3.3]heptanyl, dioxidotetrahydrothiopyranyl,dioxidothiomorpholinyl, imidazolyl, morpholinyl,octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,oxaazaspiro[3.3]heptanyl, oxaazaspiro[4.3]octanyl,oxaazaspiro[4.4]nonanyl, oxetanyl, phenyl, piperazinyl, piperazinonyl,piperidinyl, pyridinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, or triazolyl, each substituted with zero to 4substituents independently selected from F, Cl, —OH, C₁₋₃ alkyl, C₁₋₂hydroxyalkyl, C₁₋₂ alkoxy, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —NR_(x)R_(x),—C(O)NR_(x)R_(x), and —CH₂S(O)₂(C₁₋₂ alkyl).

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is an aromatic group selected from[1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazolyl,indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl, quinoxalinyl,tetrahydro[1,2,4]triazolo[1,5-a]pyrazinyl,tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,tetrahydrothiazolo[5,4-c]pyridinyl, tetrahydrothieno[2,3-c]pyridinyl,thiadiazolyl, thiazolyl, thiooxadiazolyl, and triazolyl, eachsubstituted with zero to 2 R_(14a) and zero to 3 R_(14b); and G, R₁, R₅,R_(14a), R_(14b), R_(x), R_(y), and n are defined in the first aspect.Included in this embodiment are compounds in which each R_(14a) isindependently: (i) H, F, Cl, —OH, C₁₋₅ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂hydroxyalkyl, —(CH₂)₀₋₂OCH₃, —CHR_(x)NR_(x)(C₁₋₅ alkyl),—CHR_(x)NR_(x)(C₁₋₂ cyanoalkyl), —CHR_(x)NR_(x)((CH₂)₁₋₂OCH₃),—CHR_(x)N((CH₂)₁₋₂OCH₃)₂, —CH₂NR_(x)(CH₂C≡CR_(x)),—CH₂NR_(x)CH₂CH₂NR_(x)R_(x), —(CH₂)₁₋₃CR_(x)R_(x)NR_(x)R_(x),—CH(NH₂)(CH₂)₃₋₄NR_(x)R_(x), —CH₂NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),—CH₂NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH, —CH₂NH(CH₂)₁₋₂S(O)₂OH,—CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(CH₂)₂₋₃NR_(x)R_(x),—NR_(x)C(O)(C₁₋₂ alkyl), —NR_(x)(O)(C₁₋₂ fluoroalkyl), —NR_(x)C(O)O(C₁₋₃alkyl), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —NR_(x)CH₂C(O)CH₂NR_(x)R_(x),—C(O)(C₁₋₂ alkyl), —C(O)CH₂CR_(x)R_(x)OH, —C(O)CH₂NR_(x)R_(x),—C(O)NR_(x)R_(x), —C(O)NR_(x)(CH₂CN),—C(O)NR_(x)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),—C(O)N(CH₂CH₃)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),—C(O)NR_(x)CH₂C(O)NR_(x)R_(x), —C(O)NR_(x)CH₂CH₂NR_(x)C(O)CH₃,—O(CR_(x)R_(x))₂₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or —C(O)CH₂S(O)₂(C₁₋₂alkyl); (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrazolyl,pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl, eachsubstituted with zero to 2 substituents independently selected from C₁₋₄alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —NR_(x)R_(x),—(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl), —C(O)CH₂NR_(x)R_(x),—C(O)O(C₁₋₃ alkyl), —CH₂C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, —CH₂(phenyl),—CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),—CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl, and pyridinyl;or (iii) -L₃-R_(14c); each R_(14b) is F, —CH₃, or —OCH₃; and R_(14c) isadamantanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl, diazepanyl,imidazolyl, indolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,phenyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolyl, triazolyl, or tetrazolyl, eachsubstituted with zero to 1 substituent selected from F, —OH, C₁₋₄ alkyl,C₁₋₃ hydroxyalkyl, —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl),—C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl), —C(O)O(C₁₋₂alkyl), —CH₂C(O)NR_(x)R_(y), morpholinyl, methylpiperidinyl, pyrazinyl,pyridinyl, and pyrrolidinyl.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(7b), R_(7c), n, and p are defined in the firstaspect or the second aspect. Included in this embodiment are compoundsin which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(7b), R_(7c), n, and p are defined in the firstaspect or the second aspect. Included in this embodiment are compoundsin which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(7b), R_(7c), n, and p are defined in the firstaspect or the second aspect. Included in this embodiment are compoundsin which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein R_(7b) is —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y),—C(O)(CR_(x)R_(x))₁₋₂NR_(y)(C₁₋₄ hydroxyalkyl), or—C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃); and G, R₁, R₂, R₅, R_(x),R_(y), n, and p are defined in the first aspect or the second aspect.Included in this embodiment are compounds in which G is

R₁ is —CH(CH₃)₂; and n is zero. Also included in this embodiment arecompounds in which R_(7b) is —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y).Additionally, included in this embodiment are compounds in which G is

R₁ is —CH(CH₃)₂; R_(7b) is —C(O)CH₂N(CH₃)₂ or —C(O)CH₂CH₂N(CH₃)₂ or andn is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(7b), n, and p are defined in the first aspector the second aspect.Included in this embodiment are compounds in which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(7b), n, and p are defined in the first aspector the second aspect. Included in this embodiment are compounds in whichG is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich compounds in which G is

Additionally, included in this embodiment are compounds in which n iszero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(12a), n, and p are defined in the first aspector the second aspect.Included in this embodiment are compounds in which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(12a), n, and p are defined in the first aspector the second aspect.Included in this embodiment are compounds in which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(12a), n, and p are defined in the first aspector the second aspect.Included in this embodiment are compounds in which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(12a), n, and p are defined in the first aspector the second aspect.Included in this embodiment are compounds in which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich compounds in which G is

Additionally, included in this embodiment are compounds in which n iszero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein G, R₁, R₂, R₅, R_(12a), n, and p are defined in the first aspector the second aspect.Included in this embodiment are compounds in which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich compounds in which G is

Additionally, included in this embodiment are compounds in which n iszero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein said compound has the structure:

wherein R_(12a) is —NR_(x)CR_(x)R_(x)R_(12b); R_(12b) is C₃₋₆cycloalkyl, each substituted with —S(O)₂(C₁₋₂ alkyl) or —CH₂S(O)₂(C₁₋₂alkyl); and G, R₁, R₂, R₅, R_(x), n, and p are defined in the firstaspect or the second aspect. Included in this embodiment are compoundsin which G is

and R₁ is —CH(CH₃)₂. Also included in this embodiment are compounds inwhich compounds in which G is

R₁ is —CH(CH₃)₂; R_(12b) is cyclopropyl substituted with —S(O)₂(C₁₋₂alkyl) or —CH₂S(O)₂(C₁₋₂ alkyl); and n is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein:

G is

R₁ is —CH(CH₃)₂; each R₂ is independently Cl, —CH₃, —CH₂CH₃, —CH₂OH,—CH₂CH₂OH, —CH₂CN, —OCH₃, —CH₂OCH₃, or —CH₂CH₂S(O)₂CH₃; and A is—CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom towhich they are attached form a cyclic group selected fromazaspiro[3.3]heptanyl, C₄₋₆ cycloalkyl,

each substituted with zero to 2 R_(12a); and R_(2a), R_(2b), R₅,R_(12a), n, and p are defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein: G is

R₁ is —CH(CH₃)₂; each R₂ is independently —CH₃ or —OCH₃; A is—CH₂CH₂R₁₁; and R₁₁ is azetidinyl or piperidinyl, each substituted withzero to 2 substituents independently selected from —CH₂(methyloxetanyl),—CH₂(triazolyl), —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH, —CH₂C(O)N(CH₃)₂,—CH₂CH₂S(O)₂CH₃, and oxetanyl; and R₅, n, and p are defined in the firstaspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein:

-   -   G is

A is —C(O)NR₉R₁₀; R₁ is —CH(CH₃)₂; each R₂ is —OCH₃; R₉ is —CH₂CH₂CF₃,—CH₂CH₂N(CH₃)₂, or —(CH₂)₀₋₃R_(9a); R_(9a) is piperidinyl substitutedwith —CH(CH₃)₂; R₁₀ is H, —CH₃, or —CH₂CH₃; or R₉ and R₁₀ together withthe nitrogen atom to which they are attached form a heterocyclic ringselected from piperazinyl substituted with —C(O)CH₃; and R₅, n, and pare defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein:

-   -   G is

A is —NR₇R₈; R₁ is —CH(CH₃)₂; each R₂ is independently —CH₃, —CH₂OH, or—OCH₃; R₇ and R₈ together with the nitrogen atom to which they areattached form a heterocyclic ring selected from azetidinyl,diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl,diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.1]octanyl,azaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl, diazaspiro[3.3]heptanyl,diazepanyl, diazaspiro[3.5]nonanyl, oxadiazabicyclo[3.3.1]nonanyl,piperazinyl, piperazinonyl, piperidinyl, and pyrrolidinyl, wherein saidheterocyclic ring is substituted with zero to 1 R_(7b) and zero to 2R_(7c); R_(7b) is: (i) —OH, C₁₋₆ alkyl, C₃₋₄ fluoroalkyl, C₃₋₄hydroxyalkyl, —CH₂CN, —CH₂CH₂CN, —(CR_(x)R_(x))₁₋₂OCH₃,—(CH₂)₂₋₃S(O)₂CH₃, —(CH₂)₂₋₃NHS(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(y)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl),—NH(CH₂CH₂OCH₃), —N(CH₂CH₂CN)₂, —(CH₂)₁₋₂C(O)NR_(x)R_(x),—N((CH₂)₁₋₂C(O)NR_(x)R_(x))₂, —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),—NR_(x)(CH₂CH₂S(O)₂CH₃), —C(O)(CR_(x)R_(x))₁₋₂NR_(y)R_(y),—C(O)(CR_(x)R_(x))₁₋₂NR_(x)(CH₂CH₂OCH₃), —NR_(x)R_(7d),—NR_(x)(CH₂)₁₋₂R_(7d)), —NR_(7d)R_(7d), —N((CH₂)₁₋₂R_(7d))₂,—C(O)R_(7d), or —C(O)(CR_(x)R_(x))₁₋₂R_(7d); or (ii) azetidinyl,cyclobutyl, cyclohexyl, dioxotetrahydrothiopyranyl,dioxothiomorpholinyl, morpholinyl, oxaazaspiro[4.3]octanyl, oxetanyl,piperazinyl, piperidinyl, pyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, or thiadiazolyl, each substituted with zero to 1R_(8a) and zero to 3 R_(8b); each R_(7c) is independently —CH₃ or—CH₂CN; each R_(7d) is independently azetidinyl, C₃₋₆ cycloalkyl,dioxothiaazaspiro[3.3]heptanyl, morpholinyl, oxaazaspiro[3.3]heptanyl,oxaazaspiro[4.3]octanyl, oxaazaspiro[4.4]nonyl, oxetanyl, piperidinyl,pyrimidinyl, pyrazolyl, pyrrolidinyl, tetrahydropyranyl, thiadiazolyl,or triazolyl, each substituted with zero to 2 substituents selected fromF, —OH, C₁₋₃ alkyl, —CH₂OH, —OCH₃, —NR_(x)R_(x), and —S(O)₂CH₃; R_(8a)is —OH, —CH₃, —OCH₃, —C(O)CH₃, or —C(O)OCH₃; each R_(8b) is —CH₃; andR₂, R_(x), R_(y)R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein:

-   -   G is

A is —O-L₁-R₆; L₁ is bond or —CH₂—; R₁ is —CH(CH₃)₂; each R₂ isindependently —CH₃ or —OCH₃; R₆ is: (i) —CH₃; or (ii) azetidinyl,cyclohexyl, or piperidinyl, each substituted with zero to 2 R_(6a); eachR_(6a) is independently —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂, —CH₂C(CH₃)₂OH,—N(CH₃)₂, —N(CH₂CH₂CH₃)₂, —CH₂CH₂S(O)₂CH₃, —CH₂C(O)N(CH₃)₂, ortetrahydropyranyl; and R₅, n, and p are defined in the first aspect orthe second aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein:

-   -   G is

R₁ is —CH(CH₃)₂; A is —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with thecarbon atom to which they are attached form a cyclohexyl group; R₁ is—CH(CH₃)₂; and n is zero.

One embodiment provides a compound of Formula (I) or a salt thereofwherein:

-   -   G is

R₁ is —CH(CH₃)₂; each R₂ is independently —CH₃ or —OCH₃; A is —CHR₁₂R₁₃,wherein R₁₂ and R₁₃ together with the carbon atom to which they areattached form a C₄₋₆ cyclohexyl group substituted with R_(12a);

-   -   R_(12a) is:

p is 1 or 2; and n is zero or 1. Included in this embodiment arecompounds in which R₁₂ and R₁₃ together with the carbon atom to whichthey are attached form a cyclohexyl group substituted with R_(12a).

One embodiment provides a compound of Formula (I) or a salt thereofwherein A is:

and G, R₁, R₂, R₅, R_(12a), n, and p are defined in the first aspect.Included in this embodiment are compounds in which G is

R₁ is —CH(CH₃)₂; and n is zero. Also included in this embodiment arecompounds in which G is

R₁ is —CH(CH₃)₂; R_(12a) is:

and n is zero.

One embodiment provides a compound of Formula (I) or a salt thereofwherein compound is:

One embodiment provides a compound of Formula (I) or a salt thereofwherein compound is:

One embodiment provides a compound of Formula (I) or a salt thereofwherein compound is:

One embodiment provides a compound of Formula (I) or a salt thereofwherein said compound is:

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein said compound is selected from Examples 1 to 1078.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein said compound is selected from Examples 1 to 736.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein said compound is selected from Examples 737 to 1078.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. The inventionencompasses all combinations of the aspects and/or embodiments of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phrase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “cyano” refers to the group —CN.

The term “amino” refers to the group —NH₂.

The term “oxo” refers to the group ═O.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₆ alkyl” denotes straight and branched chain alkyl groups with oneto six carbon atoms.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “cyanoalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more cyano groups. Forexample, “cyanoalkyl” includes —CH₂CN, —CH₂CH₂CN, and C₁₋₄ cyanoalkyl.

The term “aminoalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more amine groups. Forexample, “aminoalkyl” includes —CH₂NH₂, —CH₂CH₂NH₂, and C₁₋₄ aminoalkyl.

The term “hydroxyalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups. Forexample, “hydroxyalkyl” includes —CH₂OH, —CH₂CH₂OH, and C₁₋₄hydroxyalkyl.

The term “hydroxy-fluoroalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups andone or more fluorine atoms. For example, “hydroxy-fluoroalkyl” includes—CHFCH₂OH, —CH₂CHFC(CH₃)₂OH, and C₁₋₄ hydroxy-fluoroalkyl.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃-C₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom, for example, methoxygroup (—OCH₃). For example, “C₁₋₃ alkoxy” denotes alkoxy groups with oneto three carbon atoms.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy groupattached through its oxygen atom to an alkyl group, which is attached tothe parent molecular moiety, for example, methoxymethyl group(—CH₂OCH₃). For example, “C₂₋₄ alkoxyalkyl” denotes alkoxyalkyl groupswith two to four carbon atoms, such as —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂OCH₂CH₃, and —CH₂CH₂OCH₂CH₃.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wèrmuth et al.,    Ch 31, (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to TLR7/8/9, or effective to treat or prevent autoimmuneand/or inflammatory disease states, such as SLE, IBD, multiple sclerosis(MS), and Sjögren's syndrome, and rheumatoid arthritis.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as —CD₃.

UTILITY

The human immune system has evolved to defend the body frommicro-organisms, viruses, and parasites that can cause infection,disease or death. Complex regulatory mechanisms ensure that the variouscellular components of the immune system target the foreign substancesor organisms, while not causing permanent or significant damage to theindividual. While the initiating events are not well understood at thistime, in autoimmune disease states the immune system directs itsinflammatory response to target organs in the afflicted individual.Different autoimmune diseases are typically characterized by thepredominate or initial target organ or tissues affected; such as thejoint in the case of rheumatoid arthritis, the thyroid gland in the caseof Hashimoto's thyroiditis, the central nervous system in the case ofmultiple sclerosis, the pancreas in the case of type I diabetes, and thebowel in the case of inflammatory bowel disease.

The compounds of the invention inhibit signaling through Toll-likereceptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof.Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the inhibition of signaling through one ormore of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9receptor associated diseases in which cytokine levels are modulated as aconsequence of intracellular signaling.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of TLR7, TLR8, orTLR9, compounds of Formula (I) are useful in treating TLR7, TLR8, orTLR9 family receptor associated diseases, but not limited to,inflammatory diseases such as Crohn's disease, ulcerative colitis,asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosus, lupusnephritis, cutaneous lupus, psoriasis; auto-inflammatory diseasesincluding Cryopyrin-Associated Periodic Syndromes (CAPS), TNF ReceptorAssociated Periodic Syndrome (TRAPS), Familial Mediterranean Fever(FMF), adult onset stills, systemic onset juvenile idiopathic arthritis,gout, gouty arthritis; metabolic diseases including type 2 diabetes,atherosclerosis, myocardial infarction; destructive bone disorders suchas bone resorption disease, osteoarthritis, osteoporosis, multiplemyeloma-related bone disorder; proliferative disorders such as acutemyelogenous leukemia, chronic myelogenous leukemia; angiogenic disorderssuch as angiogenic disorders including solid tumors, ocularneovascularization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, keloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovascularization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Included in this embodiment are methods of treatmentin which the condition is selected from lupus including lupus nephritisand systemic lupus erythematosus (SLE), Crohn's disease, ulcerativecolitis, allograft rejection, rheumatoid arthritis, psoriasis,ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.Also included are methods of treatment in which the condition isselected from ischemia reperfusion injury, including cerebral ischemiareperfusions injury arising from stroke and cardiac ischemia reperfusioninjury arising from myocardial infarction. Another method of treatmentis one in which the condition is multiple myeloma.

In one embodiment, the compounds of Formula (I) are useful in treatingcancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large Bcell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneousdiffuse large B cell lymphoma, and primary CNS lymphoma.

In addition, the TLR7, TLR8, or TLR9 inhibitors of the present inventioninhibit the expression of inducible pro-inflammatory proteins such asprostaglandin endoperoxide synthase-2 (PGHS-2), also referred to ascyclooxygenase-2 (COX-2), IL-1, IL-6, IL-18, chemokines. Accordingly,additional TLR7/8/9 associated conditions include edema, analgesia,fever and pain, such as neuromuscular pain, headache, pain caused bycancer, dental pain and arthritis pain. The inventive compounds also maybe used to treat veterinary viral infections, such as lentivirusinfections, including, but not limited to equine infectious anemiavirus; or retrovirus infections, including feline immunodeficiencyvirus, bovine immunodeficiency virus, and canine immunodeficiency virus.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof. “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibitautoimmune disease or chronic inflammatory disease.

The methods of treating TLR7, TLR8, or TLR9 associated conditions maycomprise administering compounds of Formula (I) alone or in combinationwith each other and/or other suitable therapeutic agents useful intreating such conditions. Accordingly, “therapeutically effectiveamount” is also intended to include an amount of the combination ofcompounds claimed that is effective to inhibit TLR7, TLR8, or TLR9and/or treat diseases associated with TLR7, TLR8, or TLR9.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®);anti-malarials such as hydroxychloroquine; cytotoxic drugs such asazathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating TLR7/8/9receptor-associated conditions, including IL-1 family receptor-mediateddiseases as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parenterally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrasternallyin dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g. magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, and alginic acid; binding agents, such as,for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; andlubricating agents, such as, for example, magnesium stearate, stearicacid, and talc. Additionally, a tablet can either be uncoated, or coatedby known techniques to either mask the bad taste of an unpleasanttasting drug, or delay disintegration and absorption of the activeingredient in the gastrointestinal tract thereby sustaining the effectsof the active ingredient for a longer period. Exemplary water solubletaste masking materials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil, such as, forexample, arachis oil; olive oil; sesame oil; and coconut oil; or inmineral oil, such as, for example, liquid paraffin. An oily suspensioncan also contain at least one thickening agent, such as, for example,beeswax; hard paraffin; and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain at leastone preservative, including, but not limited to, for example, anantioxidant, such as, for example, butylated hydroxyanisol, andalpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) thereof can, forexample, be prepared as an oil-in-water emulsion. The oily phase of theemulsions comprising compounds of Formula (I) may be constituted fromknown ingredients in a known manner. The oil phase can be provided by,but is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Suitableemulsifying agents include, but are not limited to, for example,naturally-occurring phosphatides, e.g., soy bean lecithin; esters orpartial esters derived from fatty acids and hexitol anhydrides, such as,for example, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. An emulsion can also contain a sweeteningagent, a flavoring agent, a preservative, and/or an antioxidant.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride solution, tragacanth gum, and/or various buffers. Otheradjuvants and modes of administration are well and widely known in thepharmaceutical art. The active ingredient may also be administered byinjection as a composition with suitable carriers including saline,dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolventsolubilization (i.e. propylene glycol) or micellar solubilization (i.e.Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, buffers etc. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and (c) a package insert stating that the pharmaceutical composition canbe used for the treatment of an inflammatory disorder and/or anautoimmune disease (as defined previously). In another embodiment, thepackage insert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat an inflammatory disorder and/or an autoimmune disease. The articleof manufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). In one embodiment, the package insert specificallyrecites the indications for which the pharmaceutical composition hasbeen approved. The package insert may be made of any material on which aperson can read information contained therein or thereon. For example,the package insert is a printable material (e.g., paper, plastic,cardboard, foil, adhesive-backed paper or plastic, etc.) on which thedesired information has been formed (e.g., printed or applied).

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The compounds of this invention may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in thepreparation of compounds of Formula (I), can be prepared usingprocedures shown in the following Examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these Examples, are not meant to be limiting, but are meantto demonstrate how the compounds of Formula (I) can be prepared.Starting materials and reagents used in these examples, when notprepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature.

Abbreviations

-   -   Ac acetyl    -   ACN acetonitrile    -   AcOH acetic acid    -   anhyd. anhydrous    -   aq. aqueous    -   Bn benzyl    -   Bu butyl    -   Boc tert-butoxycarbonyl    -   CV Column Volumes    -   DCE dichloroethane    -   DCM dichloromethane    -   DMAP dimethylaminopyridine    -   DMF dimethylformamide    -   DMSO dimethylsulfoxide    -   EtOAc ethyl acetate    -   Et ethyl    -   EtOH ethanol    -   H or H₂ hydrogen    -   h, hr or hrs hour(s)    -   hex hexane    -   i iso    -   IPA isopropyl alcohol    -   HCl hydrochloric acid    -   HPLC high pressure liquid chromatography    -   LC liquid chromatography    -   M molar    -   mM millimolar    -   Me methyl    -   MeOH methanol    -   MHz megahertz    -   min. minute(s)    -   mins minute(s)    -   M⁺¹ (M+H)⁺    -   MS mass spectrometry    -   n or N normal    -   NBS n-bromosuccinimide    -   nm nanometer    -   nM nanomolar    -   NMP N-methylpyrrolidine    -   Pd/C palladium on carbon    -   Ph phenyl    -   PPh₃ triphenylphosphine    -   Pr propyl    -   PSI pounds per square inch    -   Ret Time retention time    -   sat. saturated    -   SFC supercritical fluid chromatography    -   TBAF tetrabutylammoniurn fluoride    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   T3P        2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide    -   2^(nd) Generation RuPhos Precatalyst:        chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    -   2^(nd) Generation Xphos precatalyst:        chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)        Analytical and Preparative HPLC Conditions;    -   QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,        1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with        10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water        with 10 mM ammonium acetate; Temperature: 50° C.; Gradient:        0-100% B over 3 minutes, then a 0.75-minute hold at 100% B;        Flow: 1.0 mL/min; Detection: UV at 220 nm.    -   QC-ACN-TFA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,        1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with        0.1% trifluoroacetic acid; Mobile Phase B: 95:5        acetonitrile:water with 0.1% trifluoroacetic acid; Temperature:        50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute        hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.    -   Method A1: L3 Acquity: Column: (LCMS) UPLC BEH C18, 2.1×50 mm,        1.7 μm particles; Mobile Phase: (A) water; (B) acetonitrile;        Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98% B        (to 1.5 min) 98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow        Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1:        UV at 220 nm; Detector 2: MS (ESI⁺).    -   Method B1: L2 Aquity(4); Column: (LCMS) UPLC BEH C18, 2.1×50 mm,        1.7 μm particles; Mobile Phase: (A) water; (B) acetonitrile;        Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98% B        (to 1.5 min) 98%-2% B (to 1.5 min); Gradient Time: 1.8 min; Flow        Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1:        UV at 220 nm; Detector 2: MS (ESI⁺).    -   Method D1 SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,        1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with        0.1% trifluoroacetic acid; Mobile Phase B: 95:5        acetonitrile:water with 0.1% trifluoroacetic acid; Temperature:        50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75 minute        hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.    -   Method D2 SCP: Column: XBridge C18, 19×200 mm, 5 μm particles;        Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium        acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM        ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5        minute hold at 100% B; Flow: 20 mL/min. Detection: UV at 220 nm.    -   Method D3 SCP: Column: XBridge C18, 19×200 mm, 5 μm particles;        Mobile Phase A: 5:95 acetonitrile: water with 0.1%        trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water        with 0.1% trifluoroacetic acid; Gradient: 6-46% B over 20        minutes, then a 4 minute hold at 100% B; Flow: 20 mL/min.        Detection: UV at 220 nm.    -   Method E1 iPAC: Column: Waters Xbridge C18 4.6×50 mm 5 um        particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM        ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with        10 mM ammonium acetate. Temperature: 50° C.; Gradient: 0-100% B        over 1 minute; Flow: 4 mL/min; Detection: UV at 220 nm.    -   Method F1 iPAC: Column: Waters Acquity BEH C18 2.1×50 mm 1.7 μm        particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%        trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water        with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient:        0-100% B over 2.20 minutes; Flow: 0.800 mL/min; Detection: UV at        220 nm.    -   Method G1: Column: Symmetry C8, (250×4.6 mm), 5 μm particles;        Mobile Phase A: 1:1 acetonitrile:TFE with 10 mM ammonium        acetate; Mobile Phase B: 1:1 acetonitrile: TFE with 10 mM        ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over        25 minutes, then a 0.75 minute hold at 100% B; Flow: 1.0 mL/min;        Detection: UV at 220 nm.    -   Method H1 (SFC): Column: Luxcellulose-4 (250×4.6 mm), 5 μm        particles; % CO₂: 50%, % Cosolvent: 50% of 0.4% isopropyl amine        in methanol; Temperature 30° C.; Flow: 120 g/min; Detection: UV        at 230 nm.    -   (A): Column-Ascentis Express C18 (50×2.1 mm-2.7 μm) Mphase A: 10        mM NH₄COOH in water: ACN (98:02); Mphase B: 10 mM NH₄COOH in        water: ACN (02:98), Gradient: 0-100% B over 3 minutes, Flow=1        mL/min.    -   (D): Kinetex XB-C18 (75×3 mm) 2.6 micron; Solvent A: 10 mM        ammonium formate in water: acetonitrile (98:02); Mobile Phase B:        10 mM ammonium formate in water: acetonitrile (02:98);        Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow        rate: 1.1 mL/min; Detection: UV at 220 nm.    -   (E): Column: Ascentis Express C18 (50×2.1) mm, 2.7 μm; Mobile        Phase A: 5:95 acetonitrile: water with 10 mM NH₄OAc; Mobile        Phase B: 95:5 acetonitrile: water with 10 mM NH₄OAc;        Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow:        1.1 mL/min.    -   (F): Column: Ascentis Express C18 (50×2.1) mm, 2.7 μm; Mobile        Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B:        95:5 acetonitrile: water with 0.1% TFA; Temperature: 50° C.;        Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min.    -   (G): Column: Waters Acquity UPLC BEH C18 (2.1×50 mm), 1.7        micron; Solvent A=100% water with 0.05% TFA; Solvent B=100%        acetonitrile with 0.05% TFA; gradient=2-98% B over 1 minute,        then a 0.5-minute hold at 98% B; Flow rate: 0.8 mL/min;        Detection: UV at 220 nm.    -   (H): Column: Acentis Express C18 (50×2.1 mm) 1.7 μm, Acentis C8        NH₄COOH 5 min. M, Mobile Phase A: 10 mM ammonium formate: ACN        (98:2), Mobile Phase B: 10 mM ammonium formate: ACN (2:98),        gradient: 20%-100% B (0-4 min); 100% B (4-4.6 min); Flow: 1        mL/min    -   (I) Column: Sunfire C18 (4.6×150) mm, 3.5 μm; Mobile Phase A:        5:95 acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5        acetonitrile: water with 0.05% TFA; Temperature: 50° C.;        Gradient: 10-100% B over 12 minutes; Flow: 1 mL/min.    -   (J) Column: Sunfire C18 (4.6×150) mm, 3.5 μm; Mobile Phase A:        5:95 acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5        acetonitrile: water with 0.05% TFA.    -   (K) Waters Acquity SDS Mobile Phase: A: water B: ACN; 5%-95% B        in 1 min; Gradient Range: 50%-98% B (0-0.5 min); 98% B (0.5        min-1 min); 98%-2% B (1-1.1 min); Run time: 1.2 min; Flow Rate:        0.7 mL/min; Analysis Time: 1.7 min; Detection: Detector 1: UV at        220 nm; Detector 2: MS (ES⁺).    -   (L) Acquity UPLC BEH C18 (3.0×50 mm) 1.7 μm. Buffer: 5 mM        ammonium acetate Mobile phase A: Buffer:ACN (95:5); Mobile phase        B:Buffer:ACN (5:95) Method: % B: 0 min-20%:1.1 min-90%:1.7        min-90%. Run time: 2.25 min; Flow Rate: 0.7 mL/min; Detection:        Detector 1: UV at 220 nm; Detector 2: MS (ES⁺).    -   (M): Kinetex SBC18 (4.6×50 mm) 5 micron; Solvent A: 10 mM        ammonium formate in water: acetonitrile (98:02); Mobile Phase B:        10 mM ammonium formate in water: acetonitrile (02:98);        Temperature: 50° C.; Gradient: 30-100% B (0-4 min), 100% B        (4-4.6 min), 100-30% B (4.6-4.7 min), 30% B (4.7-5.0 min); Flow        rate: 1.5 mL/min; Detection: UV at 220 nm.    -   (N): Column-Ascentis Express C18 (50×2.1 mm 2.7 μm) Mphase A: 10        mM NH₄COOH in water: ACN (98:02); Mphase B: 10 mM NH₄COOH in        water: ACN (02:98), Gradient: 0-100% B (0-1.7 minutes); 100% B        (1.7-3.4 minutes). Flow=1 mL/min.    -   (O) Waters Acquity SDS Column BEH C18 (2.1×50 mm) 1.7 μm. Phase        A: buffer in water; Mphase B: buffer in ACN, Gradient: 20-98% B        (0-1.25 minutes); 98% B (1.25-1.70 minutes); 98%-2% B (1.70-1.75        minutes); Flow=0.8 mL/min.    -   (P): Column: XBridge BEH XP C18 (50×2.1) mm, 2.5 μm; Mobile        Phase A: 5:95 acetonitrile: water with 10 mM NH₄OAc; Mobile        Phase B: 95:5 acetonitrile: water with 10 mM NH₄OAc;        Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow:        1.1 mL/min.    -   (Q): Column: XBridge BEH XP C18 (50×2.1) mm, 2.5 μm; Mobile        Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B:        95:5 acetonitrile: water with 0.1% TFA; Temperature: 50° C.;        Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min.    -   (R): Column-ZORBAX SB-C18 (50×4.6 mm-5.0 μm) Mphase A: 10 mM        NH₄COOH in water:ACN(98:02) Mphase B: 10 mM NH₄COOH in water:ACN        (02:98). Gradient: 0 min-30%, 4.0 min-100%, 4.6 min-100%, 4.7        min-30%. Flow\min. 1.5 mL.    -   (TS): Column: Waters Acquity UPLC BEH C18 (2.1×50 mm), 1.7        micron; Solvent A=100% water with 0.05% TFA; Solvent B=100%        acetonitrile with 0.05% TFA; gradient=2-98% B over 1 minute,        then a 0.5 minute hold at 98% B; Flow rate: 0.8 mL/min;        Detection: UV at 254 nm.    -   (DDS) Aquity: Column: (LCMS) UPLC BEH C18, 3.0×50 mm, 1.7 μm        particles; Mobile Phase: (A) 10 mM NH₄OAc: acetonitrile (95:5)        Phase B) 10 mM NH₄OAc: acetonitrile (5:95): Method: % B: 0        min-20:2 min-100:2.3 min-1001.8 min; Flow Rate: 0.7 mL/min;        Detection: Detector 1: UV at 220 nm; Detector 2: MS (ESI⁺).    -   (DDS2) Acquity: Column: (LCMS) UPLC BEH C18, 3.2×50 mm, 1.7 μm        particles; Buffer: 10 mM Ammonium Acetate Mobile Phase A:Buffer:        ACN (95:5) Mobile Phase B:Buffer:ACN (5:95); Method % B: 0        min-20%:2 min-100%:2.2 min-100%; Flow rate=0.7 mL/min,        Detection: Detector 1: UV at 220 nm; Detector 2: MS (ESI⁺).

Example 11-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine

Intermediate 1A: 2-bromo-5-hydrazinylpyridine

A solution of 6-bromopyridin-3-amine (10.0 g, 57.8 mmol) in 6 M aqueousHCl (111 mL) was cooled to 0° C. A solution of sodium nitrite (3.99 g,57.8 mmol) in water (148 mL), precooled to 0° C., was added over 5 minand the reaction mixture was stirred for 45 minutes at 0° C. Tin(II)chloride dihydrate (32.6 g, 144 mmol) was suspended in 6 M aqueous HCl(111 mL), precooled to 0° C., and was added to the reaction mixture over5 min. The reaction mixture was stirred for 60 min more at 0° C. Uponcompletion, the reaction was quenched via addition of 40% w/w solutionof KOH in water until the solution was basic as judged by pH paper. Themixture was diluted with water and DCM. The organic layer was separatedand the aqueous layer was extracted with DCM. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated toafford 2-bromo-5-hydrazinylpyridine (8.08 g, 43.0 mmol, 74.3% yield).LCMS retention time 0.41 min [A1]. MS (E⁺) m/z: 190.1 [(M+2)+H⁺]. ¹H NMR(499 MHz, CHLOROFORM-d) δ 7.98 (d, J=3.0 Hz, 1H), 7.28 (app d, J=8.5 Hz,1H), 7.10 (dd, J=8.7, 3.0 Hz, 1H), 5.25 (br app s, 1H), 3.62 (br app s,2H).

Intermediate 1B: 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine

2-bromo-5-hydrazinylpyridine (8.08 g, 43.0 mmol) was suspended in 5% v/vH₂SO₄ in water (215 mL) to form a chunky suspension. 3-Methylbutanal(5.19 mL, 47.3 mmol) was added and the suspension was stirred for 20 minat room temperature, then heated with a reflux condenser at 110° C. for20 hours. Upon completion, the mixture was cooled in an ice bath. Thereaction was quenched via the addition of 40% w/w solution of KOH inwater until the pH was basic as judged by pH paper. Water and DCM wereadded until all solids had dissolved. The organic layer was separatedand the aqueous layer was extracted twice with DCM. The combinedorganics were dried over sodium sulfate, filtered, and concentrated toafford a crude orange solid which was purified on silica gel columnchromatography (Hex/EtOAc 0-50%) to afford5-bromo-3-isopropyl-1H-pyrrolo[3,2-b] pyridine (6.19 g, 25.9 mmol, 60%yield). LCMS retention time 0.90 min [A1]. MS (E⁺) m/z: 239.1 (M+H). ¹HNMR (499 MHz, CHLOROFORM-d) δ 8.71-8.43 (m, 1H), 7.48 (d, J=8.4 Hz, 1H),7.22-7.17 (m, 2H), 3.37 (spt, J=6.8 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H).

Intermediate 1C: tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a solution of 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine (5.0 g,20.9 mmol) in THF (84 mL) were added Et₃N (4.37 mL, 31.4 mmol) and DMAP(0.255 g, 2.09 mmol). The mixture was cooled to 0° C. BOC-anhydride 30%in toluene (16.73 g, 23.0 mmol) was added in a single portion and thereaction mixture was stirred for 1 hour. Another aliquot ofBOC-anhydride 30% in toluene (2.0 g, 2.75 mmol) was added and thereaction mixture was stirred for 10 min. Upon completion, the reactionmixture was concentrated and the crude material was purified on silicagel column chromatography (Hex/EtOAc 0-40%) to afford tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (6.98 g,20.6 mmol, 98% yield). LCMS retention time 1.14 min [TS]. MS (E⁺) m/z:339.1 (M+H).

Intermediate 1D: tert-butyl5-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A suspension of tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1.05 g,3.10 mmol), tert-butyl azetidin-3-ylcarbamate (0.693 g, 4.02 mmol),RuPhos 2^(nd) Generation precatalyst (0.120 g, 0.155 mmol), and Cs₂CO₃(3.03 g, 9.29 mmol) was made in 1,4-dioxane (21 mL). The suspension wasdegassed with nitrogen for 5 min, sealed, and placed in a heating blockat 130° C. for 4 h and 20 min. Upon completion, the reaction mixture wasfiltered, concentrated and purified using silica gel columnchromatography (Hex/EtOAc 0-50%) to afford tert-butyl5-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(970 mg, 2.253 mmol, 72.8% yield). LCMS retention time 0.86 min [TS]. MS(E⁺) m/z: 431.2 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 8.19-7.98 (m,1H), 7.45-7.29 (m, 1H), 6.26 (d, J=8.8 Hz, 1H), 5.07-4.88 (m, 1H),4.68-4.51 (m, 1H), 4.35 (br t, J=7.6 Hz, 2H), 3.78 (dd, J=8.6, 5.4 Hz,2H), 3.24-3.15 (m, 1H), 1.65 (s, 9H), 1.46 (s, 9H), 1.35 (d, J=7.0 Hz,6H).

Intermediate 1E: tert-butyl5-(3-((tert-butoxycarbonypamino)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A solution containing tert-butyl5-(3-((tert-butoxycarbonypamino)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(802 mg, 1.86 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 mL, 2.42mmol) in dry THY (9.3 mL), under a nitrogen atmosphere was cooled to−78° C. and treated with LDA (2M in THF) (2.33 mL, 4.66 mmol). Themixture was warmed to −30° C. over 30 min and stirred at −30° C. for 30min, then allowed to warm slowly to 0° C. The reaction mixture wastreated with saturated aqueous ammonium chloride solution, water, andDCM. The organic layer was dried over sodium sulfate, filtered andconcentrated. The crude material was purified on silica gel columnchromatography (Hex/EtOAc 0-50%) to afford tert-butyl5-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(830 mg, 1.49 mmol, 80% yield). LCMS retention time 1.05 min [TS]. MS(E⁺) m/z: 557.7 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 7.84 (d, J=8.8Hz, 1H), 6.21 (d, J=8.8 Hz, 1H), 5.05-4.86 (m, 1H), 4.70-4.53 (m, 1H),4.34 (br t, J=7.5 Hz, 2H), 3.77 (dd, J=8.5, 5.3 Hz, 2H), 3.29-3.14 (m,1H), 1.64 (s, 9H), 1.46 (s, 9H), 1.44-1.41 (m, 18H).

Intermediate 1F:(1-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate

tert-butyl5-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(830 mg, 1.49 mmol) was heated neat under nitrogen atmosphere with slowstirring at 165° C. for 100 min. Upon completion, the material wasdissolved in DCM and concentrated to obtaintert-butyl(1-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamateas an off-white foam. LCMS retention time 0.92 min [TS]. MS (E⁺) m/z:457.7 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 8.06 (br s, 1H), 7.42 (d,J=8.8 Hz, 1H), 6.29 (d, J=8.7 Hz, 1H), 5.07-4.85 (m, 1H), 4.66-4.54 (m,1H), 4.39-4.29 (m, 2H), 3.77 (dd, J=8.7, 5.5 Hz, 2H), 3.68-3.59 (m, 1H),1.48 (d, J=7.0 Hz, 6H), 1.46 (s, 9H), 1.34 (s, 12H).

Intermediate 1G: tert-butyl(1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate

To a suspension of tert-butyl(1-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate(227 mg, 0.497 mmol),6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (124 mg, 0.547mmol), and 2^(nd) Generation XPhos precatalyst (19.6 mg, 0.025 mmol) indioxane (3.3 mL) was added 2M aqueous potassium phosphate tribasic (0.75mL, 1.49 mmol). The biphasic mixture was degassed with nitrogen for 10min. The vial was sealed and stirred at 70° C. for 2 hours. Uponcompletion, the reaction mixture was cooled to room temperature andconcentrated. The crude material was taken up in DCM and purified bysilica gel column chromatography (0-100% Hex/EtOAc) to afford tert-butyl(1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate (170 mg, 0.357 mmol, 72% yield). LCMS retentiontime 0.77 min [TS]. MS (E⁺) m/z: 476.6 (M+H).

Example 1

To a suspension of tert-butyl(1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate(170 mg, 0.357 mmol) in DCM (14 mL) at room temperature was added TFA(3.6 mL). The reaction mixture was stirred at room temperature for 30minutes. Upon completion, the reaction mixture was concentrated. Thecrude material was taken up in DMF (3.6 mL) and Et₃N (0.15 mL, 1.07mmol), tetrahydro-4H-pyran-4-one (71.5 mg, 0.714 mmol), and sodiumtriacetoxyborohydride (151 mg, 0.714 mmol) were added sequentially.After stirring for 3 hours, additional DMF (3.6 mL) and Et₃N (0.15 mL,1.07 mmol), tetrahydro-4H-pyran-4-one (71.5 mg, 0.714 mmol), and sodiumtriacetoxyborohydride (151 mg, 0.714 mmol) were added sequentially.After stirring for 2 hours more at room temperature, the reaction wasquenched by the addition of water, aqueous K₂HPO₄ 1.5M dibasic solutionand DCM. The organic layer was separated, dried over sodium sulfate,concentrated and the crude material was purified by SFC chromatographyusing the following conditions: CHIRAL IC 25×3.0 cm ID, 5 μm column;85.0 mL/min flow rate; 60/40 CO₂/methanol with 0.1% diethylamine mobilephase; 260 nm detector wavelength to obtain1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine(95 mg, 0.203 mmol, 57% yield). LCMS retention time 0.53 min [TS]. MS(E⁺) m/z: 460.7 (M+H). ¹H NMR (499 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.75(s, 1H), 8.46 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 6.27 (d, J=8.7 Hz, 1H),4.11 (t, J=7.3 Hz, 2H), 3.86-3.73 (m, 3H), 3.57 (t, J=6.8 Hz, 2H),3.32-3.25 (m, 3H), 2.84-2.75 (m, 1H), 2.58 (s, 3H), 2.15 (s, 3H),1.75-1.66 (m, 2H), 1.36 (br d, J=6.8 Hz, 6H), 1.31-1.21 (m, 2H).

Example 26-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 2A: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A suspension of tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.0 g, 5.90mmol), tert-butyl piperazine-1-carboxylate (1.32 g, 7.07 mmol), 2^(nd)generation RuPhos precatalyst (0.114 g, 0.147 mmol), and Cs₂CO₃ (4.80 g,14.7 mmol) in 1,4-dioxane (20 mL) in a reaction vial with apressure-relief septum-lined cap and stir bar was degassed with nitrogengas for 5 minutes. The reaction vial was sealed and placed in a heatingblock with stirring at 100° C. for 3 hours. An identical reactionfollowing the same protocol was set up in parallel, and the tworeactions were combined for workup and purification. Upon completion,the combined reactions were filtered and concentrated. The crudematerial was purified by silica gel column chromatography on a TeledyneIsco instrument eluting with Hex/EtOAc 0-60% to give tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(4.64 g total) as an off-white foam. LCMS retention time 1.13 [TS]. MS(E⁺) 445.3 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 8.13 (br s, 1H), 7.39(br s, 1H), 6.65 (br d, J=9.0 Hz, 1H), 3.64-3.57 (m, 4H), 3.57-3.50 (m,4H), 3.28-3.14 (m, 1H), 1.65 (s, 9H), 1.49 (s, 9H), 1.36 (d, J=6.9 Hz,6H).

Intermediate 2B: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A solution containing tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(4.64 g, 10.4 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.19 mL, 15.66mmol) in dry THF (52 mL), under a nitrogen atmosphere was cooled in adry ice/acetone bath to −78° C. and treated with LDA (2M in THF, 10.4mL, 20.8 mmol). The mixture was allowed to warm to 0° C. over the courseof 5 hours. Upon completion, the reaction was quenched by the additionof saturated aqueous NH₄Cl solution, water, and EtOAc. The organic layerwas separated, dried over magnesium sulfate, filtered and concentrated.The crude material was purified by silica gel column chromatographyeluting with Hex/EtOAc 0-50% to give tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(5.29 g, 9.27 mmol, 89% yield). LCMS retention time 1.23 [TS]. MS (E⁺)m/z: 571.2. ¹H NMR (499 MHz, CHLOROFORM-d) δ 7.86 (d, J=9.1 Hz, 1H),6.59 (d, J=9.1 Hz, 1H), 3.62-3.55 (m, 4H), 3.55-3.49 (m, 4H), 3.20 (spt,J=7.0 Hz, 1H), 1.64 (s, 9H), 1.49 (s, 9H), 1.44 (d, J=6.9 Hz, 6H), 1.42(s, 12H).

Intermediate 2C: tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate

tert-Butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(5.29 g, 9.27 mmol) was heated neat at 170° C. under a nitrogenatmosphere with stirring for 6 hours. The reaction mixture was cooled toroom temperature and remained at room temperature for 3 days. Thereaction mixture was then reheated to 170° C. under a nitrogenatmosphere with stirring for another 4 hours. Upon completion, thematerial was dissolved in DCM and concentrated to afford tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate(4.02 g, 8.55 mmol, 92% yield) as a light brown foam. The material wascarried forward without additional purification. Observed significantconversion to boronic acid on LCMS, although NMR indicated that theproduct was purely the compound. Boronic acid LCMS retention time 0.74[TS]. Boronic acid MS (E⁺) m/z: 389.1 (M+H). Product characterization:LCMS retention time 0.93 [TS]. MS (E⁺) m/z: 471.2 (M+H). ¹H NMR (499MHz, CHLOROFORM-d) δ 8.07 (s, 1H), 7.46 (d, J=8.9 Hz, 1H), 6.69 (d,J=9.1 Hz, 1H), 3.68-3.55 (m, 5H), 3.55-3.47 (m, 4H), 1.51-1.48 (m, 15H),1.34 (s, 12H).

Intermediate 2D: tert-butyl4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate(2.5 g, 5.31 mmol), 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(1.44 g, 6.38 mmol), and 2^(nd) generation XPhos precatalyst (0.209 g,0.266 mmol) in 1,4-dioxane (27 mL) was added aqueous K₃PO₄ solution (2M,7.97 mL, 15.9 mmol). The biphasic mixture was degassed with nitrogen gasfor 10 min. The reaction vessel was sealed, a line of nitrogen gas wasaffixed, and the reaction mixture was stirred at 70° C. for 3 hours.Upon completion, the reaction mixture was cooled to room temperature anddiluted with EtOAc and water. The layers were separated, and the aqueouslayer was extracted with EtOAc. The combined organic layer was driedover MgSO₄ and concentrated to afford a crude brown oil. This materialwas by silica gel column chromatography on a Teledyne Isco instrumenteluting with 0-100% Hex/EtOAc to afford tert-butyl4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate(2.31 g, 4.72 mmol, 89% yield). LCMS retention time 0.77 [TS]. MS (E⁺)m/z: 490.2 (M+H). ¹H NMR (499 MHz, DMSO-d₆) δ 10.89 (s, 1H), 8.77 (s,1H), 8.47 (s, 1H), 7.56 (d, J=8.9 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H),3.54-3.40 (m, 8H), 2.79 (spt, J=6.8 Hz, 1H), 2.58 (s, 3H), 2.16 (s, 3H),1.43 (s, 9H), 1.38 (d, J=6.9 Hz, 6H).

Example 2

To a suspension of tert-butyl4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate(223 mg, 0.455 mmol) in DCM (5 mL) at room temperature was added TFA (1mL). The reaction mixture was stirred at room temperature for 90 min andthen concentrated to afford crude6-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine.A portion (10%) of this material was purified using preparative LC/MSwith the following conditions: Column: XBridge C18, 200 mm×19 mm, 5 μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammoniumacetate; Gradient: a 0-minute hold at 5% B, 5-45% B over 20 minutes,then a 4 minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS and UVsignals. Fractions containing the product were combined and dried viacentrifugal evaporation to afford6-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(15.9 mg, 0.040 mmol). LCMS retention time 0.77 min [QC-ACN-TFA-XB]. MS(E⁺) m/z: 390.3 (M+H). NMR (500 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.69 (s,1H), 8.42 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.71 (d, J=8.9 Hz, 1H),3.46-3.36 (m, 4H), 2.94-2.85 (m, 4H), 2.85-2.77 (m, 1H), 2.59 (s, 3H),2.17 (s, 3H), 1.37 (br d, J=6.6 Hz, 6H).

Example 31-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

A solution of6-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (18.9 mg, 0.0376 mmol) in methanol was converted to the HCl saltform by adding 1 mL of 4N HCl in dioxane and concentrating to dryness.The material was taken up in methanol a second time, 1 mL of 4N HCl indioxane was added, and the material was concentrated to dryness. Thematerial was then suspended in DMF (1 mL) and dimethylglycine (28 mg,0.272 mmol), Et₃N (0.10 mL, 0.717 mmol) and T3P 50% in DMF (0.110 mL,0.188 mmol) were added. The reaction mixture was stirred for 1 hour atroom temperature. Upon completion, the reaction was quenched by additionof water, aqueous K₂HPO₄ 1.5M solution, and DCM. The organic layer wasseparated, concentrated, taken up in methanol and purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: waterwith 10 mM ammonium acetate; Gradient: a 0 minute hold at 13% B, 13-53%B over 20 minutes, then a 4 minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MS andUV signals. Fractions containing the product were combined and dried viacentrifugal evaporation to afford1-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one(12.8 mg, 0.026 mmol, 69.4% yield). LCMS retention time 0.86 min[QC-ACN-TFA-XB]. MS (E⁺) m/z: 475.3 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ10.87 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 7.57 (d, J=8.9 Hz, 1H), 6.78(d, J=8.9 Hz, 1H), 3.16 (s, 2H), 2.84-2.73 (m, 1H), 2.56 (s, 3H), 2.14(s, 3H), 1.35 (br d, J=6.7 Hz, 6H).

Example 44-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)cyclohexan-1-amine

Intermediate 4A: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a solution of tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (19.00 g,56.0 mmol),4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(16.40 g, 61.6 mmol) and 2 M aqueous potassium phosphate tribasic (84mL, 168 mmol) in THF (300 mL) was added PdCl₂ (dppf)-CH₂Cl₂ adduct(1.372 g, 1.680 mmol). The bi-phasic mixture was degassed with nitrogengas for 10 minutes and the sealed vial was stirred at 70° C. for 2hours. The reaction mixture was cooled to room temperature and dilutedwith ethyl acetate and water. The mixture was transferred to aseparatory funnel and the layers were separated. The combined organicswere washed with saturated sodium sulfate, filtered and concentrated todryness. Further purification was done by silica gel chromatography,which afforded tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(18.00 g, 45.0 mmol, 86% yield) as a light yellow solid. LCMS retentiontime 1.09 min [A1]. MS m/z: 399.5 (M+H).

Intermediate 4B: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (18.00 g, 45.0 mmol) in a Parr bottle were addedMeOH (15 mL) and 10% w/w Pd/C (1.490 g, 1.400 mmol). The vessel wasplaced on the Parr high pressure hydrogenation apparatus and pump/purgedthree times with nitrogen gas. After evacuation, the vessel wasback-filled with hydrogen gas to approximately 40 psi and the reactionmixture was allowed to shake for 2 hours. The vessel was diluted withMeOH (200 mL) and ethyl acetate (200 mL) and the contents was filteredthrough tightly packed Celite. Upon concentration, collected3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-indole (19.00 g, 47.0mmol, 100% yield) as a dark oil. LCMS retention time 0.95 min [A1]. MSm/z: 401.6 (M+H).

Intermediate 4C:3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine

A solution containing tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.600 g, 3.99 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.467 mL, 7.19mmol) in dry THF (9.99 mL), under a nitrogen atmosphere was cooled in adry-ice/acetone bath at −78° C. After stirring at −78° C. for 20minutes, LDA (2 M in THF) (5.99 mL, 11.98 mmol) was added. The mixturewas stirred at −78° C. for 30 min and allowed to warm to −30° C. over 1hour and stirred at −30° C. for 30 minutes. The reaction mixture wastreated with 1.5 M aqueous KH₂PO₄ solution. Water and ethyl acetate wereadded and the mixture was transferred to a separatory funnel. The layerswere separated and the combined organics were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated. The crudeproduct was further purified by silica gel chromatography, whichafforded tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.7 g, 3.22 mmol, 81% yield). LCMS retention time 1.00 min [A1]. MSm/z: 527.3 (M+H).

tert-Butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.7 g, 3.22 mmol) was added to a tall vial and the vial was capped. Thevial was pump/purged three times with nitrogen gas and set to heat at165° C. under a nitrogen atmosphere for 1.5 hours. The reaction mixturewas cooled to room temperature and3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(1.4 g, 3.28 mmol, 100% yield) was obtained and used as such. LCMSretention time 0.61 min [A1]. MS m/z: 345.8 (M+H) (observed the mass ofthe corresponding boronic acid).

Intermediate 4D:4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one

In a 40 mL reaction vial were added3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(0.500 g, 1.173 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.023 g, 0.035 mmol),6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.265 g, 1.173mmol) and THF (20 mL). The reaction vial was sealed and pump/purgedthree times with nitrogen gas. To this was added 2 M aqueous potassiumphosphate tribasic (1.759 mL, 3.52 mmol) and the reaction mixture washeated to 65° C. for 1 hour. Following cooling to room temperature, themixture was diluted with ethyl acetate and washed with water, then brineand dried over anhydrous sodium sulfate. The solids were filtered andthe filtrate was concentrated. The residue was further purified bysilica gel chromatography. Following concentration of the fractions,6-(3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridinewas collected as a tan solid. To this intermediate was added DCM (0.5mL), TFA (5 mL) and water (0.02 mL). The reaction vial was capped andstirred at room temperature for 4 hours, then concentrated under astream of nitrogen. To this was added 1.5 M potassium phosphatesolution, water and DCM. The mixture was poured into a separatory funneland the layers were separated. The organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated to afford4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one(0.22 g, 0.548 mmol, 47% yield). LCMS retention time 0.61 min [A1]. MSm/z: 402.2 (M+H).

Example 4

4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one (0.500 g, 1.245 mmol),(1-(methylsulfonyl)cyclopropyl) methanamine hydrochloride (0.347 g,1.868 mmol) and TEA (0.694 mL, 4.98 mmol) were mixed in DCM (5 mL). Thereaction vial was capped and the reaction mixture stirred under nitrogenovernight at room temperature. The volatiles were removed under a streamof nitrogen and the residue was placed under a nitrogen atmosphere anddiluted with MeOH (5 mL). This was cooled to −78° C. and lithiumborohydride (0.081 g, 3.74 mmol) was added. The reaction mixture wasallowed to warm to room temperature in the dry ice bath overnight. Thereaction was quenched via addition of 1.5M K₂HPO₄. Ethyl acetate wasadded and the mixture was extracted three times. The organics werewashed with saturated NaCl solution, dried over sodium sulfate, filteredand concentrated. The material was further purified by silica gelchromatography and then SFC. The major and first eluting isolate wascollected to afford4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)cyclohexan-1-amine(0.300 g, 0.555 mmol, 45% yield) as an off-white solid. HPLC retentiontime 1.44 min [Method C]. MS m/z: 535.4 (M+H). HPLC retention time 0.845min [Method D]. ¹H NMR (499 MHz, DMSO-d₆) δ 11.14-11.02 (m, 1H), 8.80(s, 1H), 8.49 (s, 1H), 7.66-7.55 (m, 1H), 7.07-6.94 (m, 1H), 3.41-3.29(m, 2H), 3.17 (d, J=2.9 Hz, 1H), 3.14-3.12 (m, 1H), 3.14 (s, 1H), 3.02(br d, J=7.0 Hz, 2H), 2.96-2.84 (m, 1H), 2.71 (tt, J=12.0, 3.5 Hz, 1H),2.45 (br d, J=2.0 Hz, 1H), 2.18 (s, 3H), 2.08-1.99 (m, 2H), 1.94 (br d,J=11.8 Hz, 2H), 1.89-1.76 (m, 1H), 1.75-1.56 (m, 2H), 1.40 (d, J=6.8 Hz,6H), 1.29-1.13 (m, 5H), 1.08-0.94 (m, 2H).

Example 52-(3,4-dimethoxyphenyl)-5-(1′-isobutyl-[1,4′-bipiperidin]-4-yl)-3-methyl-1H-pyrrolo[3,2-b]pyridine

Intermediates 5A-1 and 5A-1:5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine and5-bromo-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridine

To a mixture of 6-bromo-2-iodopyridin-3-amine (100 mg, 0.34 mmol),1,2-dimethoxy-4-(prop-1-yn-1-yl)benzene (74 mg, 0.42 mmol), lithiumchloride (18 mg, 0.42 mmol), sodium carbonate (180 mg, 1.68 mmol) andPd(dppf)Cl₂ (12.5 mg, 0.017 mmol) in a screw cap vial was added DMF (2mL). The vial was fitted with a Teflon-lined septum cap. The system wasevacuated under vacuum (via a needle from a nitrogen/vacuum manifoldline) and backfilled with nitrogen gas. The procedure was repeated threetimes. The needle was removed and the vial was heated at 100° C. for 16h. LCMS analysis shows formation of two isomers, in approximately 3:1ratio. ¹H NMR analysis suggested the major product to be5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine(5A-1). The reaction mixture was diluted with EtOAc (50 mL), poured intoa separatory funnel and washed with 10% aqueous LiCl solution (2×10 mL)and saturated aqueous NaCl solution (10 mL), dried (Na₂SO₄), filteredand the filtrate was concentrated. The crude product was dissolved in asmall amount of DCM and purified on a silica gel column chromatographywith a 15 min gradient from 0%-100% DCM/EtOAc to afford5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine(Intermediate 5A-1) that was contaminated with Intermediate 5A-2,5-bromo-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b] pyridine, m/z(303, M+1), 80 mg (67%).

Intermediate 5B: tert-butyl4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

To a mixture containing5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine(Intermediate 5A-1) and Intermediate 5A-2 (100 mg, 0.29 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(111 mg, 0.36 mmol), and Pd(dppf)Cl₂ (10.5 mg, 0.014 mmol) in a screwcap vial was added THF (2.5 mL) followed by 3M aqueous solution oftripotassium phosphate (0.10 mL, 0.3 mmol). The vial was fitted with aTeflon lined septum cap. The system was evacuated under vacuum (via aneedle from a nitrogen/vacuum manifold line) and backfilled withnitrogen gas. The procedure was repeated three times. The needle wasremoved and the vial was heated at 75° C. for 3 h. The reaction mixturewas cooled to room temperature and treated with saturated aqueous NaClsolution (5 mL) and extracted with ethyl acetate (3×10 mL). The extractswere combined, dried (Na₂SO₄), filtered and concentrated. The crudeproduct was dissolved in a small amount of DCM and purified on silicagel column chromatography eluting with a 10 min gradient from 5%-100%DCM/EtOAc. No separation was observed. A mixture of tert-butyl4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(Intermediate 5B) and the regioisomer tert-butyl4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylatewas isolated (100 mg, 77% yield), m/z (550, M+1) and was used as such insubsequent step.

Intermediate 5C: tert-butyl4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(Intermediate 5B) and regioisomer tert-butyl4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(95 mg, 0.21 mmol) was dissolved in MeOH (5 mL) and transferred to aParr bottle. The mixture was purged with nitrogen. Pearlman's Catalyst(25 mg, 0.036 mmol) was added and the bottle was pressurized withhydrogen gas (50 psi) and shaken for 22 h. The reaction mixture wasfiltered through a pad of Celite and the filtrate was concentrated. Theresulting residue was dissolved in a small amount of DCM and charged toa silica gel column, which was eluted over a 10 min gradient with 1%-5%MeOH/DCM to afford a mixture of tert-butyl4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5C)and the regioisomer tert-butyl4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(82 mg, 80%), m/z (452, M+H).

Intermediate 5D:2-(3,4-dimethoxyphenyl)-3-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine

The mixture of isomers (tert-butyl4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate(Intermediate 5C) and tert-butyl4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate(80 mg, 0.18 mmol) were suspended in 4 N HCl in dioxane (4 mL, 16.00mmol), stirred for 30 min, and concentrated to dryness. The resultingresidue was suspended in diethyl ether (1 mL) and the solids werefiltered and dried to give a mixture of2-(3,4-dimethoxyphenyl)-3-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine(Intermediate 5D) and3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridineas bis HCl salts (50 mg, 65%), m/z (352, M+H).

Example 5

To a solution containing a mixture of3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine2 HCl (Intermediate 5D) and2-(3,4-dimethoxyphenyl)-3-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine,2 HCl (30 mg, 0.07 mmol) in DMF (1 mL) was added1-isobutylpiperidin-4-one (55 mg, 0.35 mmol) followed by the addition ofsodium triacetoxyborohydride (75 mg, 0.35 mmol) and a drop of aceticacid. The reaction mixture was stirred and treated with aqueous 1 N NaOHsolution (1 mL). The mixture was extracted with ethyl acetate (3×2 mL).The extracts were combined and washed with 10% aqueous LiCl solution(2×2 mL) and concentrated. The residue was suspended in DMF (2 mL),filtered through a 0.45 micron nylon syringe filter. The crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5 μm particles; Mobile Phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 0-40%B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation to afford2-(3,4-dimethoxyphenyl)-5-(1′-isobutyl-[1,4′-bipiperidin]-4-yl)-3-methyl-1H-pyrrolo[3,2-b]pyridine, 3 TFA (25 mg, 0.03 mmol, 42%), m/z (491, M+H). Retention time,1.3 min using LCMS Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min;Detection: UV at 220 nm. ¹H NMR (500 MHz, DMSO-d₆) δ 8.31-8.17 (m, 1H),7.35 (br m, 2H), 7.33-7.28 (m, 1H), 7.18 (br d, J=8.1 Hz, 1H), 3.88 (s,3H), 3.86 (m, 3H), 2.55 (m, 3H), 0.98 (d, J=6 Hz, 6H).

Example 6N-(2-(dimethylamino)ethyl)-N-ethyl-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide

Intermediate 6A: 6-bromo-2-iodo-5-methylpyridin-3-amine

To a solution of 6-bromo-5-methylpyridin-3-amine (10 g, 53.5 mmol) inDMF (150 mL) was added NIS (12.03 g, 53.5 mmol). The resulting reactionmixture was stirred at room temperature for 12 h. The reaction mass wasdiluted with DCM (100 mL), washed with sodium thiosulfate solution (100mL), the organic layer was dried over sodium sulfate, filtered andconcentrated to get crude compound. The crude material was purified bycombiflash using 120 g silica column, the compound was eluted with 22%EtOAc in petroleum ether, the fractions was collected and concentratedto afford 6-bromo-2-iodo-5-methylpyridin-3-amine (16 g, 51.1 mmol, 96%yield) as a pale yellow solid. LCMS retention time 2.14 min [I]. MS m/z:314.1 (M+2H).

Intermediate 6B: (E)-6-bromo-2-(2-ethoxyvinyl)-5-methylpyridin-3-amine

To a solution of 6-bromo-2-iodo-5-methylpyridin-3-amine (16 g, 51.1mmol), and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(15.19 g, 77 mmol) in THF (350 mL) was added sodium hydroxide (6.14 g,153 mmol). The mixture was degassed for 10 min with nitrogen,tetrakis(triphenylphosphine)palladium (1.182 g, 1.023 mmol) was added,and the mixture was further degassed for 5 min. The resulting mixturewas stirred at 80° C. for 16 h. The reaction mass was filtered throughCelite, extracted with EtOAc (100 mL) and washed with water (2×100 mL),dried over sodium sulfate, filtered and concentrated to get crudecompound. The crude compound was purified by combiflash using 120 gsilica column, compound was eluted with 22% EtOAc in petroleum ether,the fractions were collected, concentrated to afford(E)-6-bromo-2-(2-ethoxyvinyl)-5-methylpyridin-3-amine (7 g, 27.2 mmol,53.2% yield) as a brown solid. LCMS retention time 2.41 min [D]. MS m/z:259.1 (M+2H).

Intermediate 6C: 5-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine

To a solution of (E)-6-bromo-2-(2-ethoxyvinyl)-5-methylpyridin-3-amine(7.0 g, 27.2 mmol) in methanol (300 mL) was added hydrochloric acid(8.27 mL, 272 mmol). The reaction mixture was heated at 85° C. for 16 h.The reaction mass was concentrated to afford5-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine (5.1 g, 24.16 mmol, 89%yield) as a brown solid. LCMS retention time 1.19 min [R]. MS m/z: 213.1(M+2H).

Intermediate 6D: Methyl 6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate

To a solution of 5-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine (2.0 g, 9.48mmol) in methanol (70 mL) and DMF (70 mL) were added DPPF (1.576 g, 2.84mmol) and Pd(OAc)₂ (0.425 g, 1.895 mmol). The reaction mixture wasdegassed for 10 min with nitrogen and TEA (2.64 mL, 18.95 mmol) wasadded. The mixture was stirred at 90° C. in presence of CO with 8 kgpressure for 12 h. The reaction mass was concentrated, the residue wasdissolved in DCM (100 mL), washed with water (2×100 mL), dried oversodium sulfate, filtered and concentrated to get crude compound. Thecrude compound was purified by silica gel column chromatography, thecompound was eluted with 70% ethyl acetate in petroleum ether, thefractions were collected and concentrated to afford methyl6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (1.1 g, 5.71 mmol,60.3% yield) as a pale yellow solid product. LCMS retention time 0.80min [R].

Intermediate 6E: Methyl3-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate

To a solution of methyl 6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (1.0 g, 5.26 mmol) in DMF (30 mL) wasadded dropwise NBS (0.936 g, 5.26 mmol) in DMF (15.00 mL). The resultingmixture was stirred at room temperature for 15 min. The reaction masswas poured into ice water (100 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layer was dried over sodium sulfate,filtered and concentrated to afford methyl 3-bromo-6-methyl-1H-pyrrolo[3,2-b] pyridine-5-carboxylate (1.2 g, 4.24 mmol, 81% yield) as a brownsolid. LCMS retention time 1.17 min [R]. MS m/z: 269.1 (M+2H).

Intermediate 6F: 1-tert-butyl 5-methyl3-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate

To a solution of methyl3-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (1.2 g, 4.46mmol) in THF (10 mL) were added BOC₂O (1.139 mL, 4.91 mmol), TEA (1.243mL, 8.92 mmol) and DMAP (0.109 g, 0.892 mmol) at room temperature. Thereaction mixture was stirred at the same temperature for 0.5 h. Thereaction mass was quenched with water (50 mL), extracted with ethylacetate (3×50 mL), combined organic layers was dried over sodiumsulfate, filtered and concentrated to get crude compound. The crudecompound was purified by silica gel column chromatography by elutingwith 9% EtOAc in petroleum ether, the fractions was collected andconcentrated to afford 1-tert-butyl 5-methyl3-bromo-6-methyl-1H-pyrrolo[3,2-b] pyridine-1,5-dicarboxylate (1.3 g,3.49 mmol, 78% yield) as a white solid. LCMS retention time 3.15 min[R]. MS m/z: 371.1 (M+H).

Intermediate 6G: 1-tert-butyl 5-methyl6-methyl-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate

To a solution of 1-tert-butyl 5-methyl3-bromo-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate (1.3 g,3.52 mmol) in THF (25 mL) and water (4 mL) was added potassiumphosphate, tribasic (1.840 g, 10.56 mmol). The mixture was degassed for10 minutes with nitrogen, XPhos Pd G2 (0.083 g, 0.106 mmol) was added,and the mixture was further degassed for 5 min. Next,4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.769 g,4.58 mmol) was added and the mixture was stirred at 70° C. for 12 h. Thereaction mass was filtered through Celite, extracted with EtOAc (100mL), washed with water (2×100 mL), dried over sodium sulfate andconcentrated to get crude compound. The crude compound was purified bysilica gel column chromatography. The compound was eluted with 6% EtOAcin petroleum ether, and the fractions were collected and concentrated toafford 1-tert-butyl 5-methyl 6-methyl-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate (1.1 g, 3.26 mmol, 93% yield) as apale yellow solid. LCMS retention time 3.08 min [R]. MS m/z: 331.1(M+H).

Intermediate 6H: 1-tert-butyl 5-methyl3-isopropyl-6-methyl-1H-pyrrolo[3,2-b] pyridine-1,5-dicarboxylate

To a solution of 1-tert-butyl 5-methyl6-methyl-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate(1.1 g, 3.33 mmol) in methanol (20 mL) was added Pd/C (0.6 g, 0.564mmol). The slurry was stirred at room temperature under a hydrogenbladder for 3 h. The suspension was filtered through Celite bed, thefiltrate was collected and concentrated to afford 1-tert-butyl 5-methyl3-isopropyl-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate (0.65g, 1.869 mmol, 56% yield) as an off-white solid. LCMS retention time 3.7min [R]. MS m/z: 333.1 (M+H).

Intermediate 6I: 1-tert-butyl 5-methyl2-bromo-3-isopropyl-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate

To a solution of 1-tert-butyl 5-methyl3-isopropyl-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate (0.55g, 1.655 mmol) in DCE (20 mL) was added NBS (0.442 g, 2.482 mmol)portion-wise. The resulting mixture was stirred at room temperature for16 h. The reaction mixture was diluted with water (50 mL), extractedwith DCM (2×50 mL), combined organic layers was dried over sodiumsulfate, filtered and concentrated to get crude compound. The crudecompound was purified by silica gel column chromatography, the compoundwas eluted with 5% EtOAc/petroleum ether, the fractions were collectedand concentrated to afford 1-tert-butyl 5-methyl2-bromo-3-isopropyl-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate(0.4 g, 0.807 mmol, 49% yield) as a yellow oil. LCMS retention time 4.12min [D]. MS m/z: 411.1 (M+H).

Intermediate 6J: 1-tert-butyl 5-methyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate

A solution of 1-tert-butyl 5-methyl2-bromo-3-isopropyl-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate(0.2 g, 0.486 mmol),8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine(0.147 g, 0.535 mmol) and potassium phosphate tribasic (0.254 g, 1.459mmol) in dioxane (10 mL) and water (1 mL) solvent mixture was degassedwith N₂ for 10 min. Next, PdCl₂(dppf)-CH₂Cl₂ adduct (0.040 g, 0.049mmol) was added and the mixture was degassed again for 5 min. Theresulting mixture was stirred at 80° C. for 3 h. The reaction mixturewas extracted with ethyl acetate (20 mL), washed with water (2×10 mL),brine (50 mL), dried over sodium sulfate, and concentrated to get crudeproduct. The crude product was purified by silica gel columnchromatography, the compound was eluted with 22% ethyl acetate inpetroleum ether, the fractions were collected and concentrated to afford1-tert-butyl 5-methyl 3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b] pyridine-1,5-dicarboxylate (0.2g, 0.396 mmol, 81% yield) as a brown solid. LCMS retention time 2.96 min[R]. MS m/z: 480.1 (M+H).

Intermediate 6K: Methyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate

To a solution of 1-tert-butyl 5-methyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate(0.2 g, 0.417 mmol) in DCM (2 mL) was added 4 M hydrochloric acid indioxane (0.209 mL, 0.834 mmol) drop wise. The reaction mixture wasstirred at room temperature for 1 h. The solvent was removed undervacuum and the solids were washed with diethyl ether to afford methyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate(0.15 g, 0.376 mmol, 95% yield) as a yellow solid. LCMS retention time1.91 min [R]. MS m/z: 380.1 (M+H).

Intermediate 6L:3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylicAcid

To a solution of methyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.15 g, 0.395 mmol) in methanol (2 mL), THF (2 mL) and water (1mL) solvent mixture was added lithium hydroxide (0.095 g, 3.95 mmol).The resulting mixture was stirred at room temperature for 5 h. Thevolatiles were removed under vacuum, diluted with water (5 mL) andneutralized with 1.5 N HCl. The aqueous layer was extracted with DCM(3×50 mL). The combined organic layer was dried over sodium sulfate,filtered and concentrated to afford3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylicacid (0.1 g, 0.235 mmol, 59.5% yield) as a yellow solid. LCMS retentiontime 0.98 min [R]. MS m/z: 366.1 (M+H).

Example 6

To a solution of3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxylicacid (0.02 g, 0.055 mmol) in DMF (2 mL) were addedN1-ethyl-N2,N2-dimethylethane-1,2-diamine (6.36 mg, 0.055 mmol), TEA(0.015 mL, 0.109 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) (0.023 g, 0.060 mmol) at roomtemperature. Next, the mixture was stirred at same temperature for 3 h.The reaction mixture was diluted with EtOAc (20 mL) and washed withwater (2×20 mL), dried over sodium sulfate, and concentrated to getcrude product. The crude product was purified via preparative LC/MSusing method D2, the fractions containing the product were combined anddried via centrifugal evaporation to affordN-(2-(dimethylamino)ethyl)-N-ethyl-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-5-carboxamide (7.8 mg, 0.017 mmol, 31% yield) as a pale yellowsolid. LCMS retention time 1.30 min [E]. MS m/z: 464.1 (M+H). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.49-11.45 (m, 1H), 8.66 (s, 1H), 8.52 (d,J=1.2 Hz, 1H), 7.62 (s, 1H), 7.21 (s, 1H), 4.08 (d, J=1.0 Hz, 3H), 3.90(s, 1H), 3.63 (t, J=7.1 Hz, 2H), 3.56-3.50 (m, 1H), 3.19-3.07 (m, 3H),2.72 (br. s., 2H), 2.40 (br. s., 4H), 2.32 (s, 3H), 1.97-1.89 (m, 3H),1.55-1.47 (m, 6H).

Examples 7, 8, and 93-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentan-1-one

Intermediate 7A: 3-bromocyclopent-2-en-1-one

To a stirred solution of triphenylphosphine (23.53 g, 90 mmol) in DCM(350 mL), was added bromine (4.62 mL, 90 mmol) at 0° C. The reactionmixture was stirred at same temperature for 15 min. Next, TEA (13.64 mL,98 mmol) and cyclopentane-1,3-dione (8 g, 82 mmol) in DCM (350 mL) wereadded. The mixture was stirred at room temperature for 16 h. Thereaction mass was concentrated, purified by silica gel columnchromatography, the fractions were collected and concentrated to afford3-bromocyclopent-2-en-1-one (8.9 g, 55.3 mmol, 68% yield) as an oil. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 6.57 (s, 1H), 2.99 (m, 2H), 2.52 (m, 2H).

Intermediate 7B:3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one

To a stirred solution of 3-bromocyclopent-2-en-1-one (10 g, 62.1 mmol)in 1,4-dioxane (250 mL) were added bis(pinacolato)diboron (18.93 g, 74.5mmol) and potassium acetate (12.19 g, 124 mmol). The reaction mixturewas degassed with N₂ for 10 min, PdCl₂(dppf)-CH₂Cl₂ adduct (3.55 g, 4.35mmol) was added, and the reaction mixture was stirred at 100° C. for 16h. The reaction mass was diluted with EtOAc, filtered through Celite,washed with EtOAc, the filtrate was collected and concentrated to getcrude product. The crude product was purified by ISCO using silica gelcolumn chromatography, the fractions was collected and concentrated toafford3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one(10.9 g, 52.4 mmol, 84% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 6.43 (s, 1H), 2.66 (m, 2H), 2.26 (m, 2H), 1.18 (s, 9H).

Intermediate 7C: tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine(5 g, 20.91 mmol) in THF (100 mL) were added DIPEA (41.8 mmol) andBoc-anhydride (7.28 mL, 31.4 mmol) at room temperature. The reactionmixture was stirred at the same temperature for 3 h. The reaction masswas extracted with ethyl acetate and washed with water, brine, driedover sodium sulfate and concentrated to get crude compound. The crudecompound was purified by silica gel column chromatography, the fractionswere collected and concentrated to afford tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (6.5 g,19.16 mmol, 92% yield) as an off-white solid. LCMS retention time 2.03min [L]. MS m/z: 341 (M+H).

Intermediate 7D: tert-butyl3-isopropyl-5-(3-oxocyclopent-1-en-1-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (16 g, 47.2mmol) in dioxane (400 mL) were added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one(14.72 g, 70.7 mmol) and potassium phosphate tribasic (20.02 g, 94mmol). The reaction mixture was degassed with nitrogen for 10 min, andthen PdCl₂(dppf)-CH₂Cl₂ adduct (3.85 g, 4.72 mmol) was added. Thereaction mixture was stirred at 100° C. for 16 h. The reaction mass wasfiltered through a Celite bed, washed with EtOAc and concentrated to getcrude product. The crude product was purified by silica gel columnchromatography, the fractions were collected and concentrated to affordtert-butyl3-isopropyl-5-(3-oxocyclopent-1-en-1-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(15 g, 44.1 mmol, 93% yield) as a brown solid. LCMS retention time 1.76min [L]. MS m/z: 341.6 (M+H).

Intermediate 7E: tert-butyl5-(3-hydroxycyclopentyl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of tert-butyl3-isopropyl-5-(3-oxocyclopent-1-en-1-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(10 g, 29.4 mmol) in MeOH (20 mL) at 0° C. were added nickel(II)chloride hexahydrate (0.698 g, 2.94 mmol) and NaBH₄ (4.45 g, 118 mmol).The reaction mixture was stirred at room temperature for 10 min. Thereaction was quenched with NH₄Cl solution. The reaction mixture wasconcentrated to remove methanol, the residue was extracted with EtOAc,washed with water, dried over sodium sulfate and concentrated to affordtert-butyl5-(3-hydroxycyclopentyl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(10 g, 29.0 mmol, 99% yield) as a brown solid. LCMS retention time 1.71min [L]. MS m/z: 345.6 (M+H).

Intermediate 7F: tert-butyl3-isopropyl-5-(3-oxocyclopentyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of tert-butyl5-(3-hydroxycyclopentyl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1 g, 2.90 mmol) in DCM (25 mL) was added Dess-Martin periodinane (6.16g, 14.52 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 h. The reaction mass was diluted with aqueous NaHCO₃solution, the solids were filtered, the aqueous layer was extracted withDCM, the organic layer was dried over sodium sulfate and concentrated toget crude product. The crude product was purified by silica gel columnchromatography, the fractions was collected and concentrated to affordtert-butyl3-isopropyl-5-(3-oxocyclopentyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(380 mg, 1.110 mmol, 38% yield) as an off-white solid. LCMS retentiontime 1.75 min [L]. MS m/z: 343.6 (M+H).

Intermediate 7G:3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine

To a stirred solution of tert-butyl3-isopropyl-5-(3-oxocyclopentyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.8 g, 8.18 mmol) in toluene (40 mL) were addedethylene glycol (0.692 mL, 12.26 mmol) and p-toluenesulfonic acid (0.282g, 1.635 mmol) at room temperature. Next, the mixture was stirred at130° C. for 16 h. The reaction mass was concentrated, diluted withEtOAc, and washed with saturated NaHCO₃, dried over sodium sulfate andconcentrated to get crude material. The crude material was purified bysilica gel column chromatography, the fractions were collected andconcentrated to afford3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b] pyridine(2.8 g, 7.24 mmol, 89% yield) as an off-white solid. LCMS retention time1.18 min [L]. MS m/z: 287.5 (M+H).

Intermediate 7H: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine(2.2 g, 7.68 mmol) in THF (30 mL), were added Boc-anhydride (2.68 mL,11.52 mmol), DIPEA (2.68 mL, 15.36 mmol) and DMAP (0.939 g, 7.68 mmol)at room temperature. The reaction mixture was stirred at roomtemperature for 3 h. The reaction was quenched with water. The reactionmixture was extracted with EtOAc, dried over sodium sulfate andconcentrated to get crude material. The crude material was purified byISCO using silica gel column chromatography, the fractions werecollected and concentrated to afford tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(2.8 g, 7.24 mmol, 94% yield) as a white foam. LCMS retention time 1.96min [L]. MS m/z: 387.6 (M+H).

Intermediate 7I: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.8 g, 7.24 mmol) in THF (20 mL) wasadded LDA (10.87 mL, 21.73 mmol) at −78° C. The reaction mixture wasstirred at the same temperature for 2 h, and then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.00 mL, 14.49mmol) was added slowly. The reaction mixture was brought to roomtemperature and stirred at room temperature for 1 h. The reaction wasquenched with water. The reaction mixture was extracted with EtOAc,dried over sodium sulfate and concentrated to get crude compound. Thecrude compound was purified by silica gel column chromatography, thefractions were collected and concentrated to afford tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(2.9 g, 5.66 mmol, 78% yield) as an off-white solid. LCMS retention time2.29 min [L]. MS m/z: 513.7 [M+H]⁺.

Intermediate 7J: tert-butyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a stirred solution of tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3 g, 5.85 mmol) in dioxane (100 mL) and water (2 mL) were added6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (1.602 g, 7.03 mmol)and potassium phosphate tribasic (3.73 g, 17.56 mmol). The reactionmixture was degassed with N₂ for 10 minutes and PdCl₂(dppf)-CH₂Cl₂adduct (0.478 g, 0.585 mmol) was added. The mixture was stirred at 100°C. for 16 h. The reaction mass diluted with EtOAc, filtered, and thefiltrate was concentrated to get crude product. The crude product waspurified by silica gel column chromatography, the fractions werecollected and concentrated to afford tert-butyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(2.9 g, 5.43 mmol, 93% yield) as an off-white solid. LCMS retention time1.62 min [L]. MS m/z: 534.7 [M+H]⁺.

Intermediate 7K:3-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentan-1-one

To a stirred solution of tert-butyl3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b] pyridine-1-carboxylate (2.9 g, 5.43 mmol) in DCM (20 mL) wasadded TFA (2.093 mL, 27.2 mmol) at room temperature. The reactionmixture was stirred at the same temperature for 16 h. The reactionmixture was concentrated, extracted with EtOAc, washed with water, driedover sodium sulfate and concentrated to afford3-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentan-1-one(2.1 g, 5.43 mmol, 93% yield) as a gummy solid. LCMS retention time 1.14min [L]. MS m/z: 390.6 [M+H]⁺.

Examples 7, 8, and 9

To a stirred solution of3-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentan-1-one(2.5 g, 6.42 mmol) in THF (3 mL), DMF (3 mL) were added ammonium acetate(4.95 g, 64.2 mmol), ammonium chloride (3.43 g, 64.2 mmol) and aceticacid (0.367 mL, 6.42 mmol) at room temperature. The reaction mixture wasstirred at the same temperature for 16 h, then was added NaCNBH₃ (1.210g, 19.26 mmol) and stirred another 2 h at room temperature. The reactionmass was concentrated to get crude compound. The crude compound waspurified by Prep HPLC to separate the isomers. After Prep HPLCpurifications, the fractions were collected, concentrated andlyophilized to isolate three isomers/mixtures.

-   -   Example 7: Isomer 1: diastereomer mixture, LCMS retention time        1.79 min [E]. MS m/z: 391.4 (M+H).    -   Example 8: Isomer 2: homochiral, LCMS retention time 1.78 min        [E]. MS m/z: 391.2 (M+H).    -   Example 9: Isomer 3: diastereomer mixture, LCMS retention time        1.56 min [E]. MS m/z: 391.3 (M+H).

Example 1024(3-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentyl)amino)-N-methylacetamide

To a stirred solution of3-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentan-1-amine(20 mg, 0.051 mmol) (Example 9) in DMF (2 mL) were added TEA (0.021 mL,0.154 mmol) and 2-chloro-N-methylacetamide (6.61 mg, 0.061 mmol) at roomtemperature. The reaction mixture was stirred at the same temperaturefor 16 h. The crude material was purified via preparative LC/MS usingmethod D2, the fractions containing the product were combined and driedvia centrifugal evaporation to afford2-((3-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopentyl)amino)-N-methylacetamide(3 mg). LCMS retention time 1.29 min [E]. MS m/z: 462.3 (M+H). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.30 (s, 1H), 8.63 (d, J=1.0 Hz, 1H), 8.53 (s,1H), 7.64 (d, J=8.3 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H), 7.04 (d, J=8.6 Hz,1H), 4.09 (s, 3H), 3.17-3.11 (m, 4H), 2.90 (s, 1H), 2.63 (d, J=4.9 Hz,3H), 2.32-2.23 (m, 1H), 2.00 (q, J=7.4 Hz, 2H), 1.94-1.81 (m, 3H),1.74-1.61 (m, 2H), 1.61-1.50 (m, 6H).

Example 116-(6-fluoro-3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 11A: 6-bromo-5-fluoropyridin-3-amine

To a solution of 5-fluoropyridin-3-amine (4.5 g, 40.1 mmol) in DMF (80mL) was added NBS (7.14 g, 40.1 mmol) portion wise at 0° C. The reactionmixture was stirred at room temperature for 20 min. The mixture was thenpartitioned between EtOAc (300 mL) and water (300 mL), both the layerswere separated, the organic layer was washed with saturated NaHCO₃,brine, dried over sodium sulfate, filtered and concentrated to get crudecompound. The crude compound was purified by silica gel columnchromatography, the compound was eluted with 52% ethyl acetate\hexane,the fractions were collected and concentrated to afford6-bromo-5-fluoropyridin-3-amine (4.7 g, 24.61 mmol, 61% yield) as abrown solid. LCMS retention time 0.98 min [R]. MS m/z: 193.1 (M+2H).

Intermediate 11B: tert-butyl5-amino-3-fluoro-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

tert-butyl5-amino-3-fluoro-5′,6′-dihydro-[2,4′-bipyridine]-1′(TH)-carboxylate (6.5g, 22.16 mmol, 94% yield) was prepared according to the generalprocedure described in Intermediate 5B using6-bromo-5-fluoropyridin-3-amine (4.5 g, 23.56 mmol) as the startingintermediate. LCMS retention time 1.94 min [R]. MS m/z: 293.1 (M+H).

Intermediate 11C: Tert-butyl4-(5-amino-3-fluoropyridin-2-yl)piperidine-1-carboxylate

A solution of tert-butyl5-amino-3-fluoro-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(6.5 g, 22.16 mmol) and ethyl acetate (150 mL) was purged with nitrogen(N₂). Next, Pd/C (3.30 g, 3.10 mmol) was added and the reaction mixturewas again purged with N₂ three times. Hydrogen gas (H₂) was introducedvia a balloon to the mixture. The reaction mixture was stirred at roomtemperature for 12 h. The suspension was filtered through Celite bed,the filtrate was collected and concentrated to afford tert-butyl4-(5-amino-3-fluoropyridin-2-yl)piperidine-1-carboxylate (5.8 g, 19.64mmol, 89% yield) as a yellow oil. LCMS retention time 1.68 min [R]. MSm/z: 296.1 (M+H).

Intermediate 11D: tert-butyl4-(5-amino-3-fluoro-6-iodopyridin-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(5-amino-3-fluoropyridin-2-yl)piperidine-1-carboxylate (5.6 g, 18.96 mmol) in DMF (120 mL) was addedNIS (4.27 g, 18.96 mmol) portion wise. The mixture was stirred for 2 hat room temperature. The reaction mass was diluted into water (200 mL)and extracted with ethyl acetate (3×200 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated to getcrude compound. The crude compound was purified by combiflash usingsilica gel column chromatography, the compound was eluted with 25% ethylacetate/petroleum ether, the fractions was collected and concentrated toafford tert-butyl 4-(5-amino-3-fluoro-6-iodopyridin-2-yl)piperidine-1-carboxylate (5.8 g, 13.77 mmol, 73% yield) as a brownsolid. LCMS retention time 2.46 min [R]. MS m/z: 322.1 (M+H).

Intermediate 11E: tert-butyl4-(3-fluoro-6-iodo-5-((3-methylbut-2-en-1-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(5-amino-3-fluoro-6-iodopyridin-2-yl)piperidine-1-carboxylate (3.0 g,7.12 mmol) and 3-methylbut-2-enal (2.72 mL, 28.5 mmol) in MeOH (50 mL)was added acetic acid (1 mL, 17.47 mmol). The resulting light yellowsolution was stirred at room temperature for 6 h. Next, sodiumcyanoborohydride (2.238 g, 35.6 mmol) was added at 0° C. and thereaction mixture was stirred at room temperature for 2 h. The reactionmass was concentrated to remove methanol, diluted with water (100 mL)and extracted with ethyl acetate (3×100 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated toget crude compound. The crude compound was purified by silica gel columnchromatography. The compound was eluted with 28% ethyl acetate/petroleumether, the fractions were collected and concentrated to affordtert-butyl 4-(3-fluoro-6-iodo-5-((3-methylbut-2-en-1-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (1.7 g, 3.35 mmol, 47% yield) as apale yellow oil. LCMS retention time 3.39 min [R]. MS m/z: 490.1 (M+H).

Intermediate 11F:4-(6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate

A solution of tert-butyl4-(3-fluoro-6-iodo-5-((3-methylbut-2-en-1-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (1.6 g, 3.27 mmol), potassiumcarbonate (0.497 g, 3.60 mmol) and tetrabutylammonium bromide (3.16 g,9.81 mmol) in DMF (20 mL) was degassed for 10 minutes with nitrogen, andPd(OAc)₂ (0.073 g, 0.327 mmol) was added. The reaction mixture wasfurther degassed for 5 min. The reaction mixture was stirred at 80° C.for 14 h. The reaction mixture was diluted with ethyl acetate (200 mL).The reaction mixture was washed with water (2×100 mL), brine (100 mL),dried over sodium sulfate, and concentrated to get crude product. Thecrude product was purified by silica gel column chromatography, thecompound was eluted with 65% ethyl acetate/petroleum ether, thefractions were collected, and concentrated to afford tert-butyl4-(6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate (0.5 g, 1.383 mmol, 42% yield) as a pale yellowoil. LCMS retention time 3.80 min [R]. MS m/z: 362.1 (M+H).

Intermediate 11G: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a solution of tert-butyl4-(6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate (0.3 g, 0.830 mmol) in THF (2 mL) were addedTEA (0.231 mL, 1.660 mmol), BOC₂O (0.212 mL, 0.913 mmol), and DMAP(0.020 g, 0.166 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith water (100 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated to get crude compound. The crude compound was purified bysilica gel column chromatography by eluting with 9% EtOAc: petroleumether, the fractions were collected and concentrated to afford t-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.33 g, 0.715 mmol, 86% yield) as a white solid. LCMS retention time3.92 min [R]. MS m/z: 462.1 (M+H).

Intermediate 11H: tert-butyl2-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-butyl2-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (0.6 g, 0.766 mmol, 58.9% yield) wasprepared according to the general procedure described in Intermediate 61using tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.6 g, 1.300 mmol) as the starting intermediate. LCMS retention time4.32 min [D]. MS m/z: 541.1 (M+H).

Intermediate 11I: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.25 g, 0.359 mmol, 64% yield) was prepared according to the generalprocedure described in Intermediate 7J using tert-butyl2-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.3 g, 0.555 mmol) as the starting material. LCMS retention time 4.16min [R]. MS m/z: 593.1 (M+H).

Example 11

To a solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.25 g, 0.422 mmol) in DCM (2 mL) was added 4 M hydrochloric acid indioxane (2 mL, 8.00 mmol) drop-wise. The reaction mixture was stirred atroom temperature for 1 h. The reaction mass was concentrated to getcrude product. The crude product was purified via preparative LC/MSusing method D2, the fractions containing the product were combined anddried via centrifugal evaporation to afford6-(6-fluoro-3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (11.3 mg, 0.029 mmol, 7% yield) as a pale yellow solid.LCMS retention time 1.26 min [E]. MS m/z: 393.1 (M+H). NMR (400 MHz,DMSO-d₆) δ ppm 11.45 (br. s., 1H), 8.85 (s, 1H), 8.54 (s, 1H), 7.62 (s,1H), 7.53 (d, J=11.0 Hz, 1H), 3.89 (s, 1H), 3.18-3.13 (m, 2H), 2.82-2.72(m, 2H), 2.63 (s, 3H), 2.06 (s, 2H), 1.83-1.76 (m, 2H), 1.53 (d, J=6.8Hz, 6H).

Example 394-(1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)morpholine

Intermediate 39A: tert-butyl3-((tert-butyldiphenylsilyl)oxy)azetidine-1-carboxylate

tert-Butyl 3-hydroxyazetidine-1-carboxylate (2.05 g, 11.8 mmol) wasdissolved in DCM (40 mL), and imidazole (1.61 g, 23.7 mmol) andtert-butylchlorodiphenylsilane (3.58 g, 13.0 mmol) were addedsequentially. The reaction mixture was stirred for 17 hours at roomtemperature. Upon completion, the reaction was quenched by the additionof water and DCM. The layers were separated, and the aqueous layer wasextracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated to afford a clear oil. This materialwas purified by silica gel column chromatography on a Teledyne Iscoinstrument eluting with Hex/EtOAc 0-15% to afford tert-butyl3-((tert-butyldiphenylsilyl) oxy)azetidine-1-carboxylate (11.8 mmol).LCMS retention time 1.22 [TS]. MS (E+) m/z: 823.4 (2M+H). NMR (499 MHz,CHLOROFORM-d) δ 7.63-7.57 (m, 4H), 7.46-7.41 (m, 2H), 7.41-7.35 (m, 4H),4.52 (tt, J=6.6, 4.7 Hz, 1H), 3.97-3.90 (m, 2H), 3.89-3.83 (m, 2H), 1.42(s, 9H), 1.06 (s, 9H).

Intermediate 39B: 3-((tert-butyldiphenylsilyl)oxy)azetidine

Intermediate 39A (11.8 mmol)) was dissolved in DCM (20 mL), cooled to 0°C., and precooled 0° C. TFA (20 mL) was added. When the reaction wascompleted as judged by LCMS analysis, the reaction mixture wasconcentrated, redissolved in DCM, and made basic by the addition of 1 Maqueous NaOH solution. The aqueous layer was extracted with DCM, and thecombined organics were dried over sodium sulfate, filtered, andconcentrated to afford 3-((tert-butyldiphenylsilyl)oxy)azetidine (11.8mmol). LCMS retention time 0.84 [TS]. MS (E⁺) m/z: 312.2 (M+1). ¹H NMR(499 MHz, CHLOROFORM-d) δ 7.64-7.59 (m, 4H), 7.44-7.40 (m, 2H),7.39-7.34 (m, 4H), 4.62 (quin, J=6.5 Hz, 1H), 3.70-3.61 (m, 2H),3.55-3.47 (m, 2H), 1.05 (s, 9H).

Intermediate 39C: tert-butyl5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1 g, 2.95 mmol), 3-((tert-butyldiphenylsilyl)oxy)azetidine (1.19 g,3.83 mmol), 2^(nd) generation RuPhos precatalyst (0.114 g, 0.147 mmol),and Cs₂CO₃ (2.88 g, 8.84 mmol) were suspended in 1,4-dioxane (20 mL) ina reaction vial with a pressure-relief septum-lined cap and a stir bar.The suspension was degassed with nitrogen gas for 10 minutes and thensealed and placed in a heating block with stirring at 130° C. for 45minutes. Upon completion, the reaction mixture was cooled to roomtemperature, filtered, concentrated and purified by silica gel columnchromatography on a Teledyne Isco instrument eluting with Hex/EtOAc0-30% to afford tert-butyl5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1.42 g, 2.49 mmol, 85% yield). LCMS retentiontime 1.09 [TS]. MS (E⁺) m/z: 570.4 (M+H). NMR (499 MHz, CHLOROFORM-d) δ8.06 (br s, 1H), 7.69-7.63 (m, 4H), 7.47-7.33 (m, 7H), 6.23 (d, J=8.8Hz, 1H), 4.79-4.71 (m, 1H), 4.14 (dd, J=8.6, 6.5 Hz, 2H), 3.95 (dd,J=8.7, 5.0 Hz, 2H), 3.25-3.15 (m, 1H), 1.64 (s, 9H), 1.36 (d, J=6.8 Hz,6H), 1.07 (s, 9H).

Intermediate 39D; tert-butyl5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A solution containing tert-butyl5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.42 g, 2.49 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.661 mL, 3.24mmol) in dry THF (12.5 mL), under a nitrogen atmosphere was cooled in adry ice/acetone bath to −78° C. and treated with LDA (2M in THF, 1.87mL, 3.74 mmol). The mixture was allowed to warm to −30° C. over 30 minand stirred at −30° C. for 30 min. Upon completion, the reaction wasquenched by the addition of saturated aqueous NH₄Cl solution, water, andDCM. The organic layer was separated, dried over sodium sulfate,filtered and concentrated. The crude material was purified by silica gelcolumn chromatography on a Teledyne Isco instrument loading in hexanesand eluting with Hex/EtOAc 0-40% to afford tert-butyl5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.64 g, 2.36 mmol, 95% yield). LCMS retention time 1.14 [TS]. MS (E+)m/z: 696.5 (M+H).

Intermediate 39E:5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine

tert-Butyl5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.64 g, 2.36 mmol) was heated neat at 165° C. in a vial with apressure-relief septum-lined cap and a stir bar under an atmosphere ofnitrogen with a line of nitrogen gas. The reaction mixture was heatedfor a two hours, sat at room temperature overnight, and then was heatedfor another hour for a total of three hours of neat heating at 165° C.Upon completion, the reaction mixture was dissolved in DCM andconcentrated to obtain5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(1.40 g, 2.35 mmol, 100% yield) as a light brown foam. Note: observedpartial conversion to the corresponding boronic acid on LCMS, althoughNMR indicated that the product was purely the compound. Boronic acidLCMS retention time 0.98 [TS]. Boronic acid MS (E+) m/z: 514.1 (M+H).Product characterization: LCMS retention time 1.07 [TS]. MS (E+) m/z:596.1 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.69-7.63(m, 4H), 7.46-7.37 (m, 7H), 6.27 (d, J=8.8 Hz, 1H), 4.80-4.70 (m, 1H),4.13 (dd, J=8.7, 6.4 Hz, 2H), 3.95 (dd, J=8.7, 5.2 Hz, 2H), 3.64 (spt,J=7.0 Hz, 1H), 1.50 (d, J=7.0 Hz, 6H), 1.35 (s, 12H), 1.07 (s, 9H).

Intermediate 39F:6-(5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

To a mixture of5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(500 mg, 0.839 mmol),6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (209 mg, 0.923mmol), and 2^(nd) generation XPhos precatalyst (33.0 mg, 0.042 mmol) in1,4-dioxane (6 mL) was added aqueous K₃PO₄ (2M, 1.26 mL, 2.52 mmol). Thebiphasic mixture was degassed with nitrogen gas for 10 min. The reactionvial was sealed with a pressure-relief septum-lined cap and stirred at70° C. for 1.5 hours. Upon completion, the reaction mixture was cooledto room temperature, concentrated, and suspended in DCM for purificationby silica gel column chromatography on a Teledyne Isco instrumenteluting with Hex/EtOAc 0-100% to afford6-(5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(355 mg, 0.577 mmol, 68.8% yield). LCMS retention time 0.99 [TS]. MS(E+) m/z: 615.2 (M+H).

Intermediate 39G:1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-ol

To a stirred solution of6-(5-(3-((tert-butyldiphenylsilyl)oxy)azetidin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(355 mg, 0.577 mmol) in THF (3.8 mL) was added TBAF (0.69 mL, 0.69mmol). The reaction mixture was stirred at room temperature for 1 hour.Upon completion, the reaction mixture was concentrated directly, takenup in DCM, and purified by silica gel column chromatography on aTeledyne Isco instrument eluting with 0-100% Hex/EtOAc to afford1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-ol(195 mg, 0.518 mmol, 90% yield). LCMS retention time 0.59 [TS]. MS(E^(±)) m/z: 377.1 (M+H).

Intermediate 39H:1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-ylmethanesulfonate

To a stirred solution of1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-ol(190 mg, 0.505 mmol) in THF (10 mL) at 25° C. was added Et₃N (176 μL,1.26 mmol) and MsCl (43.3 μL, 0.555 mmol) sequentially. The reactionmixture was stirred for 2 hours at room temperature, and then anotheraliquot each of Et₃N (176 μL, 1.26 mmol) and MsCl (43.3 μl, 0.555 mmol)were added. Upon addition of these aliquots, the reaction reachedcompletion quickly. The reaction was quenched by the addition of waterand DCM. The layers were separated, and the aqueous layer was extractedwith DCM. The combined organic layer was dried over sodium sulfate,filtered, and concentrated to afford1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-ylmethanesulfonate (219 mg, 0.482 mmol, 95% yield. LCMS retention time0.64 [TS]. MS (E+) m/z: 455.1 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ8.55 (br s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.56 (d, J=8.7 Hz, 1H),6.32 (d, J=8.7 Hz, 1H), 5.42 (tt, J=6.4, 4.5 Hz, 1H), 4.47-4.40 (m, 2H),4.19 (dd, J=10.3, 4.6 Hz, 2H), 3.08 (s, 3H), 2.87 (spt, J=6.9 Hz, 1H),2.56 (s, 3H), 2.12 (s, 3H), 1.39 (d, J=6.8 Hz, 6H).

Example 39

A solution of1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-ylmethanesulfonate (22 mg, 0.048 mmol), Et₃N (0.034 mL, 0.242 mmol) andmorpholine (0.013 mL, 0.145 mmol) in DMF (1 mL) was heated to 80° C.with stirring for 2.5 hours and the reaction was cooled to roomtemperature. Another aliquot of morpholine (0.050 mL, 0.574 mmol) wasadded, and the reaction was heated to 100° C. for 20 hours. Uponcompletion, the reaction was diluted with DMF and purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with10-mM ammonium acetate; Gradient: 19-59% B over 20 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min. The fractions containing theproduct were combined and dried via centrifugal evaporation to give4-(1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidin-3-yl)morpholine(5.3 mg, 0.011 mmol, 23% yield). LCMS retention time 0.77[QC-ACN-TFA-XB]. MS (E+) m/z: 446.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ10.85 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 6.28(d, J=8.7 Hz, 1H), 3.99 (br t, J=7.2 Hz, 2H), 3.73 (br t, J=6.4 Hz, 2H),3.64-3.54 (m, 4H), 3.27-3.18 (m, 1H), 2.80 (dt, J=13.7, 6.9 Hz, 1H),2.58 (s, 3H), 2.35 (br s, 4H), 2.15 (s, 3H), 1.35 (br d, J=6.4 Hz, 6H).

Example 966-(3-isopropyl-5-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

6-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (18.93 mg, 0.0376 mmol) and Et₃N (0.1 mL, 0.717 mmol) were mixed inDMF (1 mL) at room temperature. Formaldehyde (37 wt % in water, 25 μL,0.336 mmol) was added to the reaction vial followed by sodiumtriacetoxyborohydride (36 mg, 0.170 mmol). After 1 hour, the reactionwas quenched by the addition of water, aqueous 1.5 M K₂HPO₄ solution,and DCM. The organic layer was separated, concentrated, taken up inmethanol and purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 15% B, 15-55% B over 19 minutes, then a 5-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fractioncollection was triggered by UV signals. The fractions containing theproduct were combined and dried via centrifugal evaporation to afford6-(3-isopropyl-5-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(13.9 mg, 0.033 mmol, 88% yield). LCMS retention time 1.31 min[QC-ACN-AA-XB]. MS (E⁺) m/z: 404.3 (M+H). Select NMR peaks: ¹H NMR (500MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 7.59 (d,J=8.9 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 2.84-2.73 (m, 1H), 2.59 (br s,3H), 2.57 (s, 3H), 2.14 (s, 314), 1.35 (br d, J=6.7 Hz, 6H).

Example 1051-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazin-1-yl)-2-methylpropan-2-ol

6-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (18.93 mg, 0.0376 mmol) and potassium carbonate (27 mg, 0.195 mmol)were mixed in ethanol (1 mL). 2,2-dimethyloxirane (24 mg, 0.333 mmol)was added to the reaction mixture. The reaction vessel was sealed andheated to 80° C. with stirring for 3 hours. Upon completion, thereaction mixture was cooled to room temperature, filtered, concentrated,taken up in DMSO and purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 27% B, 27-67% B over 20 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fractioncollection was triggered by MS and UV signals. The fractions containingthe product were combined and dried via centrifugal evaporation toafford1-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperazin-1-yl)-2-methylpropan-2-ol(9.9 mg, 0.021 mmol, 57.0% yield). LCMS retention time 1.92[QC-ACN-AA-XB]. MS (E⁺) m/z: 461.9 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ10.81 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 7.53 (d, J=8.9 Hz, 1H), 6.72(d, J=8.9 Hz, 1H), 3.54-3.38 (m, 4H), 2.82-2.72 (m, 1H), 2.66 (br s,4H), 2.57 (s, 3H), 2.26 (s, 2H), 2.16 (s, 3H), 1.36 (br d, J=6.7 Hz,6H), 1.12 (s, 6H).

Example 1641-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-(oxetan-3-yl)pyrrolidin-3-amine

Intermediate 164A:5-bromo-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine

A solution containing tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (3.00 g,8.84 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.71 mL, 13.27 mmol) in dry THF (30 mL) under a nitrogen atmosphere wascooled in a dry ice/acetone bath at −78° C. and treated with LDA (2M inTHF) (5.53 mL, 11.05 mmol). The mixture was stirred at −78° C. for 30minutes and allowed to warm to −30° C. over 1 hour and stirred at −30°C. for 30 minutes. The reaction was treated with 1.5 M aqueous KH₂PO₄solution, water, and DCM. The layers were separated and the organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude product was purified by silica gelchromatography to afford tert-butyl5-bromo-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.LCMS retention time 1.32 min [Method A]. MS m/z: 465.1 (M+H). Thismaterial was transferred to a 40 mL tall vial, which was capped andflushed with nitrogen gas. The reaction mixture was stirred and heatedat 160° C. for 1.5 hours and5-bromo-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(2.1 g, 5.75 mmol, 65% yield) was obtained as a yellow solid. Note:material converted to the free boronic acid on LCMS and was observed assuch: LCMS retention time 0.85 min [Method A]. MS m/z: 282.9/284.9(M+H/(M+2)+H).

Intermediate 164B: tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

In a 40 mL reaction vial was added5-bromo-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(1.500 g, 4.11 mmol),6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (1.14 g, 4.90 mmol),and 2nd generation XPhos precatalyst (0.162 g, 0.205 mmol) and THF (20mL). The reaction vial was sealed and pump/purged three times withnitrogen gas. Potassium phosphate, tribasic (6.16 mL, 12.33 mmol) wasadded and the reaction mixture was heated to 65° C. for 1 hour. Themixture was diluted with ethyl acetate and washed with water, then brineand dried over anhydrous sodium sulfate. The solids were filtered offand the filtrate was concentrated. To this was added THF (20 mL), acrystal of DMAP and BOC-anhydride (0.954 mL, 4.11 mmol). The reactionmixture was stirred for 18 hours and was concentrated under a stream ofnitrogen gas. The residue was purified by silica gel chromatography toafford tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.1 g, 5.75 mmol, 65% yield) as a tan solid.LCMS retention time 1.22 min [Method A]. MS m/z: 486.2 (M+H).

Intermediate 164C:1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)pyrrolidin-3-one

In a 1 dram vial was added tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.150 g, 0.310 mmol), 2nd generation RuPhos precatalyst (0.024 g, 0.031mmol), 1,4-dioxa-7-azaspiro[4.4]nonane (0.060 g, 0.464 mmol) and cesiumcarbonate (0.303 g, 0.929 mmol). The reaction vial was capped with aTeflon-lined cap and pump/purged two times with nitrogen gas. To this,under nitrogen, was added dioxane (2 mL) and the reaction vial waspump/purged three times and was set to heat at 100° C. for 18 hours. Thereaction mixture was diluted with ethyl acetate and filtered throughCelite. The filtrate was concentrated and purified by silica gelchromatography to afford tert-butyldimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylateas a tan oil. LCMS retention time 1.06 min [Method A]. MS m/z: 533.4(M+H). To this was added TFA (2 mL) and 1 drop of water and the reactionmixture was stirred for 6 hours, then was concentrated under a stream ofnitrogen gas. The residue was diluted with 1.5M K₂HPO₄ solution and DCM.The mixture was transferred to a separatory funnel and the layers wereseparated. The organics were dried over anhydrous sodium sulfate,filtered and concentrated to afford1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)pyrrolidin-3-one(50 mg, 0.206 mmol, 42% yield) as a brownish solid. LCMS retention time0.79 min [Method A]. MS m/z: 389.3 (M+H).

Example 164

In a 1 dram vial was added1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)pyrrolidin-3-one(0.025 g, 0.064 mmol), DCM (1 mL) and oxetan-3-amine (0.014 g, 0.193mmol). The reaction mixture was stirred for 4 hours at 25° C., thensodium triacetoxyborohydride (0.041 g, 0.193 mmol) was added. Thereaction mixture was stirred for 12 hours at the same temperature. Thesample was concentrated, diluted with DMF, filtered and was purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with10-mM ammonium acetate; Gradient: 10-50% B over 24 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing theproduct were combined and dried via centrifugal evaporation to afford1-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-(oxetan-3-yl)pyrrolidin-3-amineas a racemic mixture (6.7 mg, 0.0150 mmol, 23% yield), m/z (446.4, M+H).Retention time, 1.450 min using LCMS Column: Waters Acquity UPLC BEHC18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM.

Example 3682-((4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide

Intermediate 368A:4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylcyclohexanamine

4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one(0.015 g, 0.037 mmol) and methylamine in THF (0.093 mL, 0.187 mmol) weremixed in DMF (1 mL) and AcOH (6.42 μL, 0.112 mmol). To this was addedsodium triacetoxyborohydride (0.040 g, 0.187 mmol). The reaction mixturewas stirred for 12 hours. The reaction was quenched via addition of 1.5MK₂HPO₄. Ethyl acetate was added and the mixture was extracted threetimes (3×50 mL). The organics were combined, washed with saturated NaClsolution, dried over anhydrous sodium sulfate, filtered and concentratedto obtain Intermediate 368A. Intermediate 368A was separated intocis/trans isomers according to the conditions below. Alternatively,crude Intermediate 368A could be carried forward as a cis/trans mixturefor further derivatization and subsequent separation to afford theindividual derivatized isomers.

Example 367 (Isomer 1) and Example 369 (Isomer 2)

Intermediate 368A was purified and separated into the cis and transisomers via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the individual isomers were dried via centrifugal evaporationto afford the following:

Example 367: Isomer 1:4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylcyclohexanamine(4.3 mg, 0.00970 mmol, 26% yield), m/z (417.2, M+H). Retention time,1.204 min [Method C]. ¹H NMR (500 MHz, DMSO-d₆) δ 11.16-10.99 (m, 1H),8.79 (s, 1H), 8.48 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.07 (d, J=8.2 Hz,1H), 3.18 (s, 1H), 2.90 (br s, 2H), 2.71 (br s, 1H), 2.60 (s, 2H), 2.55(s, 1H), 2.32 (s, 2H), 2.18 (s, 2H), 2.06 (br d, J=14.3 Hz, 1H), 1.86(br s, 2H), 1.81-1.72 (m, 1H), 1.65 (br s, 2H), 1.56-1.47 (m, 1H), 1.40(br d, J=6.7 Hz, 4H), 1.24 (s, 3H), 1.00 (d, J=6.4 Hz, 1H), 0.86 (br t,J=6.7 Hz, 1H).

Example 369: Isomer 2:4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylcyclohexanamine(2.4 mg, 0.00576 mmol, 11% yield), m/z (417.2, M+H). Retention time,1.323 min [Method C]. ¹H NMR (500 MHz, DMSO-d₆) δ 11.19-11.01 (m, 1H),8.78 (s, 1H), 8.48 (s, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.01 (br d, J=8.5Hz, 1H), 2.96-2.83 (m, 1H), 2.72 (br t, J=11.9 Hz, 1H), 2.60 (s, 3H),2.39 (s, 3H), 2.18 (s, 2H), 2.11-1.92 (m, 4H), 1.83 (br s, 3H),1.75-1.58 (m, 2H), 1.40 (br d, J=6.7 Hz, 6H), 1.34-1.20 (m, 2H).

Example 368

To a 1 dram vial was added Intermediate 368a,4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylcyclohexanamine(0.020 g, 0.048 mmol), DCM (1 mL) and DBU (0.025 mL, 0.164 mmol). Thematerial went into solution and 2-chloro-N,N-dimethylacetamide (0.018 g,0.144 mmol) was added. The reaction mixture was stirred at 25° C. for 18hours. The mixture was then concentrated under a steam of nitrogen gas,was diluted with 90:10:0.1 acetonitrile:water:TFA, filtered and waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over24 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the product were combined and dried via centrifugalevaporation to afford2-((4(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamideas a single cyclohexyl isomer (0.9 mg, 0.00160 mmol, 3.3% yield), m/z(502.3, M+H). Retention time, 1.249 min using LCMS Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10 mM. ¹H NMR (500 MHz, DMSO-d₆) δ 11.23-11.03(m, 1H), 8.81 (s, 1H), 8.49 (s, 1H), 7.67-7.50 (m, 1H), 7.00 (d, J=8.3Hz, 1H), 3.06 (s, 2H), 2.93-2.79 (m, 4H), 2.77-2.66 (m, 2H), 2.60 (s,4H), 2.23 (s, 3H), 2.18 (s, 3H), 1.99 (br d, J=12.6 Hz, 2H), 1.89 (br s,2H), 1.66 (br d, J=11.9 Hz, 3H), 1.50-1.35 (m, 9H).

Example 424 and Example 430N-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)-N-methyloxetan-3-amine

Intermediate 368A,4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylcyclohexanamine(0.025 g, 0.060 mmol) and oxetan-3-one (8.65 mg, 0.120 mmol) were mixedin DCM (1 mL). To this was added AcOH (0.344 μL, 6.00 μmol) and sodiumtriacetoxyborohydride (0.038 g, 0.180 mmol). The mixture was stirred for2 hours at 25° C. then was quenched via addition of 1.5M K₂HPO₄solution. Additional DCM was added and the contents were transferred toa separatory funnel and the layers were separated. The combined organicswere washed with a saturated NaCl solution, dried over anhydrous sodiumsulfate, filtered, concentrated and purified via preparative LC/MS withthe following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: 10-50% B over 24 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the products were combinedand dried via centrifugal evaporation to afford the following resolvedproducts:

Example 424: Isomer 1:N-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1h-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)-N-methyloxetan-3-amine(2.5 mg, 0.00519 mmol, 7% yield), m/z (473.2, M+H). Retention time,1.384 min [Method C]. ¹H NMR (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.78(s, 1H), 8.48 (s, 1H), 7.60 (br d, J=8.2 Hz, 1H), 7.00 (br d, J=8.2 Hz,1H), 4.52 (br d, J=6.7 Hz, 4H), 4.04-3.90 (m, 1H), 3.18 (br s, 2H),2.95-2.84 (m, 1H), 2.68 (br s, 1H), 2.60 (s, 3H), 2.45-2.32 (m, 1H),2.18 (s, 6H), 1.97 (br d, J=11.3 Hz, 2H), 1.75 (br d, J=11.6 Hz, 2H),1.64 (br d, J=12.8 Hz, 2H), 1.40 (br d, J=6.7 Hz, 8H).

Example 430: Isomer 2:N-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)-N-methyloxetan-3-amine(6.8 mg, 0.0140 mmol, 18% yield), m/z (473.3, M+H). Retention time,1.537 min [Method C]. ¹H NMR (500 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.82(s, 1H), 7.96 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H),4.48 (quin, J=6.3 Hz, 4H), 3.95-3.81 (m, 1H), 3.10 (br s, 1H), 2.90 (s,2H), 2.61 (s, 2H), 2.41-2.16 (m, 6H), 2.07 (s, 3H), 1.90 (br s, 2H),1.74 (br s, 3H), 1.45 (br d, J=7.0 Hz, 7H).

Example 4386(1r,4r)-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide

Intermediate 438A: 2-thia-6-azaspiro[3.3]heptane 2,2-dioxidehydrochloride

Intermediate 438B: 6-tosyl-2-oxa-6-azaspiro[3.3]heptane

To a solution of EtOH (500 mL) and3-bromo-2,2-bis(bromomethyl)propan-1-ol (14.00 g, 43.1 mmol) was added4-methylbenzenesulfonamide (16.23 g, 95 mmol) at 25° C. and the reactionmixture was refluxed for 20 h. The solvent was removed by evaporationand to this was added 100 mL of an 8% NaOH solution. The suspension wasstirred for another 2 hours, filtered and the yellow filter cake wasrinsed with water and dried overnight through air to give6-tosyl-2-oxa-6-azaspiro[3.3]heptane (9.05 g, 35.7 mmol, 83% yield) as alight yellow solid. LCMS retention time 0.72 min [Method A]. MS m/z:254.3 (M+H).

Intermediate 438C: (3-(bromomethyl)-1-tosylazetidin-3-yl) methanol

To a suspension of 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (10.50 g, 41.5mmol) in diethyl ether (300 mL) at 0° C. was added a solution ofhydrobromic acid in acetic acid (7.16 mL, 43.5 mmol) in 20 mL of ether,dropwise. The resulting solution was stirred at 0° C. for 2 hours, then1N NaOH was added to pH=8. The phases were separated and the aqueousphase was extracted with ethyl acetate (3×150 mL). The combined organicswere dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to afford the (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (13.5g, 36.4 mmol, 88% yield) as a solid. LCMS retention time 0.80 min[Method A]. MS m/z: 336.2 (M+H)

Intermediate 438D: 3,3-bis(bromomethyl)-1-tosylazetidine

In a 500 mL round bottom flask (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (14.44 g, 38.9 mmol) was dissolved in DCM (250 mL) and carbontetrabromide (21.93 g, 66.1 mmol) was added. The solution was cooled inan ice bath and triphenylphosphine (17.34 g, 66.1 mmol) was added in oneportion. The resulting mixture was stirred at 0° C. for 2 hours, thenwarmed to 25° C. and stirred for 4 hours. Diethyl ether (200 mL) wasadded and the resulting yellow precipitate was filtered and discarded.The filtrate was concentrated under reduced pressure and purified bysilica gel chromatography to afford3,3-bis(bromomethyl)-1-tosylazetidine (11 g, 27.7 mmol, 71.2% yield) asa white solid. LCMS retention time 0.99 min [Method A]. MS m/z: 398.1(M+H)

Intermediate 438E: 6-tosyl-2-thia-6-azaspiro[3.3]heptane

To a solution of 3,3-bis(bromomethyl)-1-tosylazetidine (36.0 g, 91 mmol)in a mixture of acetonitrile (30 mL) and water (5 mL) was added sodiumsulfide nonahydrate (43.5 g, 181 mmol) and the reaction mixture wasstirred at 50° C. for 4 hours. This was concentrated under reducedpressure and diluted with EtOAc (100 mL) and 1N NaOH solution (30 mL).The phases were separated and the aqueous phase was extracted with EtOAc(2×100 mL). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated to give6-tosyl-2-thia-6-azaspiro[3.3]heptane (21.2 g, 79 mmol, 87% yield) as ayellow solid. LCMS retention time 0.9 min [Method A]. MS m/z: 270.2(M+H).

Intermediate 438F: 6-tosyl-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide

To a 100 mL round bottom flask was added6-tosyl-2-thia-6-azaspiro[3.3]heptane (3.50 g, 12.99 mmol) and DCM (50mL). The mixture was cooled to 0° C. and mCPBA (8.74 g, 39.0 mmol) wasadded. The reaction mixture was warmed to 25° C. and stirred for 4hours. The mixture was concentrated, diluted with MeOH (50 mL) andstirred for 30 minutes. The suspension was filtered and the solid waswashed with additional MeOH and dried through air to afford6-tosyl-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (3.5 g, 11.61 mmol,90% yield) as a white solid. LCMS retention time 0.72 min [Method A]. MSm/z: 302.2 (M+H)

Intermediate 438A: 2-thia-6-azaspiro[3.3]heptane 2,2-dioxidehydrochloride

In a 250 mL round bottom flask was dissolved6-tosyl-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (0.750 g, 2.489 mmol)in MeOH (30 mL). Fresh magnesium (0.907 g, 37.3 mmol) was added and thereaction was heated at 50° C. for 16 hours with vigorous stirring. Thereaction mixture was then concentrated to near dryness and the resultinggreyish material was suspended in diethyl ether (100 mL). Sodium sulfatedecahydrate (8.02 g, 24.89 mmol) was added and the slurry was stirredfor 1 hour, then filtered, dried over anhydrous sodium sulfate andfiltered. The white solid was dissolved in DCM (2 mL) and 4M HCl/dioxane(5 mL) was added. A white solid precipitated out and the suspension wasallowed to sit for 30 minutes, then concentrated. Diethyl ether wasadded and the suspension was stirred for 30 minutes. The solid wasfiltered through a frit and washed with diethyl ether to afford2-thia-6-azaspiro[3.3]heptane 2,2-dioxide HCl (0.250 g, 1.361 mmol,54.7% yield) as a white solid.

Example 438

4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one (Intermediate 4D, 0.755 g, 1.880 mmol),2-thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (0.518 g, 2.82mmol) and DBU (0.567 mL, 3.76 mmol) were mixed in DCM (6 mL) with aceticacid (1.076 μl, 0.019 mmol). The reaction vial was capped. The reactionmixture was stirred overnight at 25° C. The volatiles were removed undera stream of nitrogen gas and the residue was diluted with MeOH (1 mL).The reaction mixture was cooled to −78° C. and lithium borohydride (2Min THF) (2.82 mL, 5.64 mmol) was added drop-wise over 10 minutes. Themixture was stirred at the same temperature for 1 hour, and then thereaction was quenched by addition of 1.5 M aqueous K₂HPO₄. DCM was addedand the mixture was transferred to a separatory funnel and the layerswere separated. The aqueous layer was extracted with DCM (3×50 mL) andthe combined organics were washed with a saturated sodium chloridesolution, dried over anhydrous sodium sulfate, filtered and concentratedto afford 1.4 g of crude material. The crude material was purified bypreparative SFC using the following conditions: Sample preparation: 1.4g/36 mL MeOH:DCM(4:1), 38.88 mg/mL; Column: Cellulose-4 (3×25 cm, 5 μm,#121391); temperature=35° C.; flow rate: 200 mL/min; BPR pressure: 100bars; mobile Phase: CO₂/MeOH:MeCN (1:1) w 0.1% NH₄OH (45/55); separationprogram: Stack injection; Injection: 3.5 mL with cycle time: 4.2 mins;throughput: 1.9 g/hr; Detector Wavelength: 220 nm. The fractionscontaining the product were concentrated and further purified using thefollowing procedure: Approximately 900 mg of the white solid from SFCpurification was dissolved in a boiling mixture of ethylacetate:methanol (4:1). The flask was capped and maintained at roomtemperature for 48 hours. A white solid was filtered off and washed withethyl acetate, followed by MeOH. The solid was dried and collected toafford6-((1r,4r)-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide (0.57 g, 1.070 mmol, 56.9% yield) as a white solid. LCMSretention time 0.56 min [Method A]. MS m/z: 533.5 (M+H).

Exploration of reductive amination conditions in the preparation ofExample 438:

*cis:trans:**alcohol Reducing Agent Solvent Temp. ratio NaBH₄ DMF 25° C.8:1:0 NaBH₄ DCM 25° C. 8:1:0 NaBH₄ MeOH −78° C. No Reaction LiBH₄ MeOH−78° C. 1:3:1 LiBH₄ ***DCM/ 25° C./−78° C. 1:6:1 MeOH *Approximateratios were obtained via HPLC. **Alcohol ratio refers to the ketonereduction to the alcohol. ***Iminium was pre-generated in DCM at 25° C.,The reduction was performed at −78° C. in MeOH.

Alternate Synthesis of Example 438 Intermediate 1A:2-bromo-5-hydrazinylpyridine

To a solution of 6-bromopyridin-3-amine (50 g, 289 mmol) in HBr in 47%water (570 mL) at 0° C. in a 5 L multi-neck round bottom flask, wasadded dropwise a solution of sodium nitrite (19.94 g, 289 mmol) in water(312.5 mL). After 1 hour at 0° C., a solution of tin (II) chloridedihydrate (157 g, 694 mmol) in HBr, 47% in water (345 mL) is slowlyadded at 0° C. After this addition was complete, the reaction mixturewas allowed to stir for 1 hour at 0° C. The solid was collected byfiltration and dried for 30 minutes through air and then washed withdiethyl ether (500 mL). Following drying to remove the diethyl ether,2-bromo-5-hydrazineylpyridine dihydrobromide (65 g, 186 mmol, 64.3%yield) was collected as a solid. LCMS retention time 0.68 min [DDS]. MSm/z: 188.1 (M+H).

Intermediate 1B: 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine

Isovaleraldehyde (23.70 mL, 220 mmol) was added to a solution of2-bromo-5-hydrazineylpyridine dihydrobromide (70 g, 200 mmol) insulfuric acid (70 mL, 1313 mmol) in water (630 mL) and the reactionmixture was stirred for 30 minutes at room temperature. The reactionmixture was heated to 110° C. and stirred for 18 hours. The reactionmixture was diluted with ethyl acetate (2000 mL) and washed with water(200 mL). The separated organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduce pressure to afford5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine (200 mmol) as brownliquid. Material carried forward without additional purification. LCMSretention time 1.64 min [DDS]. MS m/z: 241.1 (M+H).

Intermediate 1C: tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a solution of 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine (55 g,193 mmol) in THF (550 mL) at 0° C. was added TEA (42.4 mL, 304 mmol)over 10 minutes followed by the addition of DMAP (2.360 g, 19.32 mmol).At 0° C., BOC-anhydride 30% in toluene (16.73 g, 23.0 mmol) was added ina single portion and the reaction mixture was stirred for 1 hour.Another aliquot of Boc-anhydride (67.3 mL, 290 mmol) was added and thereaction mixture was stirred for 18 hours at 25° C. Upon completion, thereaction mixture was concentrated in vacuo and the crude material waspurified on silica gel chromatography to afford tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (37 g, 104mmol, 53.6% yield). LCMS retention time 1.59 min [DDS]. MS m/z: 339.0(M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (d, J=8.5 Hz, 1H), 7.71 (s, 1H),7.52 (d, J=8.5 Hz, 1H), 3.27-3.08 (m, 1H), 1.63 (s, 9H), 1.32 (d, J=7.0Hz, 6H).

Intermediate 4A: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a 1000 mL sealed tube was added tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (42 g, 124mmol) and4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(34.6 g, 130 mmol) in a mixture of tetrahydrofuran (360 mL) and water(42 mL). To this was added potassium phosphate tribasic (52.6 g, 248mmol) and 2^(nd) generation X-Phos precatalyst (3.90 g, 4.95 mmol. Thebi-phasic mixture was degassed with nitrogen gas for 10 minutes and thesealed vial was stirred at 70° C. for 12 hours. The reaction mixture wascooled to room temperature and diluted with ethyl acetate and water. Themixture was transferred to a separatory funnel and the layers wereseparated. The combined organics were washed with saturated sodiumchloride, dried over anhydrous sodium sulfate, filtered and concentratedto dryness. Further purification was done by silica gel chromatographyto afford tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(39.00 g, 98.0 mmol, 79% yield) LCMS retention time 2.53 min [DDS2]. MSm/z: 399.5 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (d, J=9.0 Hz, 1H),8.48 (s, 1H), 8.41 (d, J=9.0 Hz, 1H), 7.50-7.40 (m, 1H), 7.24-7.14 (m,1H), 4.82 (s, 2H), 4.75 (s, 2H), 4.20 (s, 3H), 3.69-3.59 (m, 1H),3.36-3.29 (m, 1H), 3.17-3.01 (m, 2H), 2.74 (s, 1H), 2.48 (s, 1H), 2.25(d, J=7.0 Hz, 3H), 2.08 (s, 9H).

Intermediate 4B: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(80 g, 201 mmol) in ethyl acetate (800 mL) was added 10% w/w Pd-C (29.9g, 28.1 mmol). The flask was placed under vacuum and pump/purged withnitrogen gas. After evacuation, the vessel was back-filled with hydrogengas via a hydrogen filled bladder and the reaction mixture was allowedto stir for 2-3 hours. The vessel was diluted with ethyl acetate and thecontents was filtered through tightly packed Celite. Upon concentration,the crude material was purified by silica gel chromatography to affordtert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(67.00 g, 167.0 mmol, 83% yield) as a yellow oil. LCMS retention time1.86 min [DDS2]. MS m/z: 401.4 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ8.22-8.08 (m, 1H), 7.58-7.52 (m, 1H), 7.21-7.13 (m, 1H), 4.01 (d, J=7.0Hz, 1H), 3.89-3.86 (m, 2H), 3.84 (s, 2H), 2.25-2.18 (m, 2H), 2.18-2.10(m, 2H), 1.89-1.72 (m, 6H), 1.60 (s, 3H), 1.59-1.53 (m, 1H), 1.32 (d,J=7.0 Hz, 4H), 1.23-1.18 (m, 1H), 1.16-1.13 (m, 1H), 1.18-1.13 (m, 2H),1.16-1.12 (m, 2H)

Intermediate 4E: tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

In 1 L round bottom flask was added tert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(45 g, 112 mmol) in tetrahydrofuran (675 mL) under a nitrogenatmosphere. The reaction mixture was cooled in a dry ice/acetone bath to−78° C. To this was added slowly LDA (112 mL, 225 mmol) and the mixturewas stirred at −78° C. for 45-50 min.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34.5 mL, 169 mmol)was added and the reaction mixture was stirred at the same temperaturefor 1-2 hours. The reaction was quenched with saturated aqueous KH₂PO₄solution at the same temperature, then water and ethyl acetate wereadded and the mixture was transferred to a separatory funnel. The layerswere separated and the combined organics were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated. The crudeproduct was further purified by silica gel chromatography to affordtert-butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(35.0 g, 66.5 mmol, 60% yield). LCMS retention time 2.05 min [DDS2]. MSm/z: 527.5 (M+H).

Intermediate 4C:3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine

tert-Butyl3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(35 g, 66.5 mmol) was added to a 500 mL round bottom flask. The reactionmixture was pump/purged three times with nitrogen gas and set to heat at150° C. under a nitrogen atmosphere for 7-8 hours. The reaction mixturewas cooled to room temperature, then 200 mL petroleum ether was addedand distilled completely. The solid was washed with ether and dried for1-2 hours to afford3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(23.0 g, 54.0 mmol, 81% yield) as a yellow solid. LCMS retention time1.47 min [DDS2]. MS m/z: 427.5 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ8.25 (br s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.03(t, J=2.6 Hz, 4H), 3.83-3.71 (m, 1H), 2.98-2.86 (m, 1H), 2.13-1.90 (m,6H), 1.79 (br s, 2H), 1.56 (d, J=6.9 Hz, 6H), 1.39 (s, 12H).

Intermediate 4F:6-(3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

In a 1 L sealed tube,3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(22.5 g, 52.8 mmol), and6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (11.93 g, 52.8 mmol)were dissolved in tetrahydrofuran (225 mL) and water (22.5 mL).Potassium phosphate tribasic (33.6 g, 158 mmol) was added, then themixture was purged with nitrogen gas for 5 minutes.1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.720 g,2.64 mmol) was added and the reaction mixture was heated to 70° C. for2-3 hours. Following cooling to room temperature, the mixture wasdiluted with ethyl acetate and washed with water, then brine and driedover anhydrous sodium sulfate. The solids were filtered and the filtratewas concentrated. The residue was further purified by silica gelchromatography to afford6-(3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(19.0 g, 42.6 mmol, 81% yield) as an off-white solid. LCMS retentiontime 1.70 min [DDS2]. MS m/z: 446.6 (M+H). NMR (300 MHz, DMSO-d₆) δ11.04 (s, 1H), 8.80 (s, 1H), 8.48 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.01(d, J=8.6 Hz, 1H), 3.91 (t, J=2.8 Hz, 4H), 3.09-3.08 (m, 1H), 2.97-2.74(m, 2H), 2.60 (s, 3H), 2.18 (s, 3H), 1.97-1.77 (m, 5H), 1.75-1.58 (m,2H), 1.41 (d, J=6.9 Hz, 6H)

Intermediate 4D:4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one

In a 1 L sealed tube,6-(3-isopropyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(36 g, 81 mmol) was mixed in tetrahydrofuran (660 mL). Next, HCl (101mL, 1212 mmol) was added and the mixture was stirred at room temperaturefor 18 hours. To the reaction mixture was added saturated potassiumphosphate solution to pH=8 and ethyl acetate (500 mL×2). The mixture waspoured into a separatory funnel and the layers were separated. Theorganics were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated. The crude material was treated with petroleumether (200 mL) and stirred for 15 minutes. The filter cake was washedwith additional petroleum ether and dried to afford4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one(30.0 g, 74.8 mmol, 92% yield) as an off-white solid. LCMS retentiontime 1.53 min [DDS2]. MS m/z: 402.4 (M+H). NMR (400 MHz, DMSO-d₆) δ11.12-10.98 (m, 1H), 8.78 (s, 1H), 8.47 (s, 1H), 7.58 (d, J=8.5 Hz, 1H),6.98 (d, J=8.5 Hz, 1H), 4.31 (s, 4H), 2.97-2.81 (m, 1H), 2.59 (s, 2H),2.17 (s, 3H), 2.13-2.00 (m, 1H), 1.97-1.76 (m, 4H), 1.72-1.53 (m, 2H),1.39 (d, J=6.5 Hz, 3H), 1.18-0.98 (m, 2H)

Example 438

To a 2 L round bottom flask was added4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one(29 g, 72.2 mmol), 2-thia-6-azaspiro[3.3]heptane 2,2-dioxidehydrochloride (19.90 g, 108 mmol), DCM (435 mL) and acetic acid (0.413mL, 7.22 mmol). To this was added DBU (32.7 mL, 217 mmol) and thereaction mixture was stirred for 18 hours at room temperature. Thevolatiles were removed under reduced pressure and the resulting residuewas dissolved in methanol (435 mL). The mixture was cooled to −78° C.and to this was added lithium borohydride (54.2 mL, 217 mmol) viasyringe over 30-40 minutes. The reaction was stirred at −78° C. for 2hours. The reaction mixture was allowed to warm to room temperature andwas quenched with a saturated potassium phosphate solution. This wasdiluted with water (150 mL), extracted with ethyl acetate (300 mL×3),dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude material was taken into 100 mL of IPA and stirred for 30-40minutes at 50° C. The mixture was cooled to room temperature, filtered,and washed with 20 mL of IPA to give an off-white solid containing 90%of the trans product. Further purification was performed by preparativeSFC using the following conditions: Sample preparation: 18 g of crudematerial; Column: Lux Cellulose-4 (250×4.6) mm 5 μm; temperature=30° C.;BPR pressure: 100 bar; mobile Phase: 0.2% NH₄OH in ACN:MeOH (1:1);Injection: 10 mL; Detector Wavelength: 220 nm. The fractions containingproduct were concentrated and further purified using the followingprocedure: This material was then trapped with (methanol, THF,acetonitrile) and the solid was taken into 30% aqueous IPA 60 mL (18 mLwater: 48 mL IPA), then heated to 70° C. for 1 hour. The mixture wasbrought to room temperature, filtered, washed with IPA (20 mL) and driedfor 10-12 hours to afford6-((1r,4r)-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide (16.0 g, mmol, 41.4% yield)) as a white solid. LCMSretention time 1.31 min [DDS2]. MS m/z: 533.4 (M+H). ¹H NMR (499 MHz,DMSO-d₆) δ 11.16-11.02 (m, 1H), 8.80 (s, 1H), 8.48 (s, 1H), 7.59 (d,J=8.2 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 4.32 (s, 4H), 4.10 (q, J=5.2 Hz,1H), 3.17 (d, J=5.2 Hz, 314), 2.88 (quin, J=6.9 Hz, 1H), 2.74-2.56 (m,4H), 2.17 (s, 3H), 2.13-1.99 (m, 1H), 1.98-1.88 (m, 2H), 1.84 (br d,J=10.7 Hz, 2H), 1.71-1.55 (m, 2H), 1.40 (d, J=6.9 Hz, 6H), 1.19-0.97 (m,2H).

Alternate synthesis of Intermediate 438A: 2-thia-6-azaspiro[3.3]heptane2,2-dioxide hydrochloride

Intermediate 438B: 6-tosyl-2-oxa-6-azaspiro[3.3]heptane

KOH (276 g, 4926 mmol) was dissolved in ethanol (2.5 L) and to thissolution was added 3-bromo-2,2-bis(bromomethyl)propan-1-ol (500 g, 1539mmol) and 4-methylbenzenesulfonamide (316 g, 1847 mmol). The reactionmixture was heated to 85° C. for 2 days, then cooled to room temperatureand to this was added 8% sodium hydroxide solution (2.5 L). The mixturewas stirred for 2 hours and a white solid was filtered off. Thecollected solid was stirred in water (1 L) and filtered. This processwas repeated 3 times. The solid was then stirred with methanol (1 L),filtered and dried through air to afford6-tosyl-2-oxa-6-azaspiro[3.3]heptane (250 g, 984 mmol, 64% yield) as anoff-white solid. LCMS retention time 1.16 min [DDS2]. MS m/z: 254.2(M+H)

Intermediate 438C: (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol

To a suspension of 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (240 g, 947mmol) in diethyl ether (2.5 L) at 0° C. was added a solution ofhydrobromic acid in acetic acid (171 mL, 1042 mmol) in diethyl ether(1.5 L) drop-wise. The resulting solution was stirred at 0° C. for 30minutes, warmed to room temperature and stirred for an additional 2hours. To this was added a 10% sodium bicarbonate solution until pH=8was reached. MTBE was added and the phases were separated. The aqueousphase was extracted with ethyl acetate, and the combined organics werewashed with water and then brine, then dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to afford the(3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (302 g, 904 mmol, 95%yield) as a white solid. LCMS retention time 1.34 min [DDS2]. MS m/z:334.1/336.1 (M+H). ¹H NMR (300 MHz, CHLOROFORM-d) δ 7.83-7.64 (m, 2H),7.47-7.32 (m, 2H), 3.69 (d, J=5.0 Hz, 2H), 3.65-3.59 (m, 2H), 3.58-3.52(m, 2H), 3.46 (s, 2H), 2.48 (s, 3H), 1.71 (t, J=5.0 Hz, 1H).

Intermediate 438D: 3,3-bis(bromomethyl)-1-tosylazetidine

In a 1 L round bottom flask,(3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (54 g, 162 mmol) wasdissolved in DCM (540 mL) and carbon tetrabromide (86 g, 259 mmol wasadded. The solution was cooled in an ice bath and triphenylphosphine(67.8 g, 259 mmol) was added portion-wise. The resulting mixture waswarmed to 25° C. and stirred for 18 hours. The reaction mixture wasconcentrated and ethyl acetate was added and the mixture was stirred for10 minutes, then a white solid was filtered off. The filtrate wasconcentrated under reduced pressure and purified by silica gelchromatography to afford 3,3-bis(bromomethyl)-1-tosylazetidine (50 g,126 mmol, 78% yield) as a white solid. LCMS retention time 1.87 min[DDS2]. MS m/z: 398.1 (M+H). NMR (400 MHz, CHLOROFORM-d) δ 7.81-7.70 (m,2H), 7.42 (d, J=8.0 Hz, 2H), 3.61 (s, 4H), 3.55 (s, 4H), 2.50 (s, 3H).

Intermediate 438E: 6-tosyl-2-thia-6-azaspiro[3.3]heptane

To a solution of 3,3-bis(bromomethyl)-1-tosylazetidine (35 g, 88 mmol)in a mixture of acetonitrile (350 mL) and water (35 mL) was added sodiumsulfide nonahydrate (106 g, 441 mmol) and the reaction mixture wasstirred at 50° C. for 3 hours. The reaction mixture was concentratedunder reduced pressure and diluted with EtOAc and water. The phases wereseparated and the aqueous phase was extracted with EtOAc. The combinedorganics were washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated to give 6-tosyl-2-thia-6-azaspiro[3.3]heptane(21 g, 78 mmol, 88% yield) as a white solid LCMS retention time 1.56 min[DDS2]. MS m/z: 270.1 (M+H). ¹H NMR (300 MHz, CHLOROFORM-d) δ 7.76-7.68(m, 2H), 7.37 (d, J=7.9 Hz, 2H), 3.78 (s, 4H), 3.14 (s, 4H), 2.46 (s,3H).

Intermediate 438F: 6-tosyl-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide

To a 4 L flask was added 6-tosyl-2-thia-6-azaspiro[3.3]heptane (175 g,650 mmol) and DCM (2.75 L). The mixture was cooled to 0° C. and mCPBA(320 g, 1299 mmol) was added over 30 minutes, then the reaction mixturewas warmed to 25° C. and stirred for 3 hours. The mixture was dilutedwith DCM and washed with a 5% NaOH solution (3×1 L). The combinedorganics were washed with water and brine, then dried over anhydroussodium sulfate, filtered and concentrated. The crude material waspurified by silica gel chromatography to afford6-tosyl-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (135 g, 449 mmol, 69%yield) as a white-solid. LCMS retention time 1.16 min [DDS2]. MS m/z:302.1 (M+H). NMR (300 MHz, CHLOROFORM-d) δ 7.79-7.66 (m, 2H), 7.40 (d,J=7.9 Hz, 2H), 4.12 (s, 4H), 3.97 (s, 4H), 2.47 (s, 3H).

Intermediate 438A: 2-thia-6-azaspiro[3.3]heptane 2,2-dioxidehydrochloride

6-tosyl-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (40 g, 133 mmol) andmagnesium (32.3 g, 1327 mmol) were taken in dry methanol (1600 mL) andheated to 50° C. for 18 hours. The mixture was cooled to roomtemperature and stirred for an additional 18 hours. To this was addedsodium sulfate decahydrate (428 g, 1327 mmol) and DCM (2 L) and themixture was stirred for 1 hour and filtered. The solid was suspended inDCM (2 L), stirred and the suspension was filtered. The combinedfiltrate was concentrated to near dryness. Residual water was evaporatedand the resulting solid was taken in DCM (200 mL). The suspension wasfiltered through sodium sulfate and the filtrate collected. To this wasadded 4M HCl in dioxane (25 mL) and the resulting solid was filtered andwashed with DCM to afford 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide HCl(15.2 g, 65% yield) as a white solid. ¹H NMR (499 MHz, DMSO-d₆) δ9.47-9.16 (m, 2H), 4.50 (s, 4H), 4.30-4.09 (m, 4H).

Example 4916-(3-isopropyl-5-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 491A:5-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine

tert-Butyl 5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylatewas prepared according to the general method described above forIntermediate 1C. A solution containing tert-butyl5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (3.00 g,10.18 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.11 mL, 15.27 mmol) in dry THF (25 mL), under a nitrogen atmosphere,was cooled in a dry ice/acetone bath at −78° C. and treated with LDA (2Min THF) (6.36 mL, 12.72 mmol). The mixture was stirred at −78° C. for 30minutes and allowed to warm to −30° C. over 1 hour and stirred at −30°C. for 30 minutes. The reaction mixture was treated with 1.5 M aqueousKH₂PO₄ solution, water and DCM. The organic layer was collected, driedover anhydrous sodium sulfate, filtered and concentrated. The crudeproduct was purified by silica gel chromatography to afford tert-butyl5-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.LCMS retention time 1.31 min [Method A]. MS m/z: 420.8/422.3 (M+H). Thismaterial was transferred to a 40 mL vial and flushed with nitrogen gas.The mixture was sealed and was heated at 160° C. for 1.5 hours to afford5-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(2.4 g, 7.49 mmol, 74% yield) as a tan solid. LCMS retention time 1.16min [Method A]. MS m/z: 321.1/323.1 (M+H).

Intermediate 491B: tert-butyl5-chloro-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

In a 40 mL reaction vial was added5-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(1.000 g, 3.12 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.041 g, 0.062 mmol)6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.705 g, 3.12 mmol)and THF (40 mL). The reaction was sealed and pump/purged three timeswith nitrogen gas. To this was added aqueous potassium phosphate,tribasic (2M, 4.68 mL, 9.36 mmol) and the reaction was heated to 65° C.for 1 hour. The mixture was diluted with ethyl acetate and washed withwater, then brine and dried over anhydrous sodium sulfate. The solidswere filtered off and the filtrate was concentrated. The crude materialwas purified by silica gel chromatography to give6-(5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridineas a tan/brown solid. To this was added THF (100 mL) and BOC-anhydride(0.724 mL, 3.12 mmol). A crystal of DMAP was added and the reaction wascapped and stirred for 18 hours at 25° C., then concentrated underreduced pressure. To this residue was added DCM and water and themixture was transferred to a separatory funnel. The layers wereseparated and the combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to afford 5a:tert-butyl5-chloro-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.9 g, 2.046 mmol, 65% yield). LCMS retention time 1.17 min [Method A].MS m/z: 440.1 (M+H)

Example 491

To a solution of tert-butyl5-chloro-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.20 g, 0.455 mmol), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate(0.119 g, 0.341 mmol), and potassium phosphate, tribasic (0.682 mL,1.364 mmol) in THF (300 mL) was added PdCl₂(dppf)-CH₂Cl₂ adduct (9.28mg, 0.011 mmol) and the biphasic mixture was degassed with nitrogen for10 minutes. The reaction vessel was sealed. The reaction mixture wasstirred at 90° C. for 2 hours, then was diluted with ethyl acetate andwashed with saturated sodium chloride solution. The organic layer wasdried with magnesium sulfate, filtered and concentrated. The crudematerial was purified by silica gel chromatography to give tert-butyl5-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.LCMS retention time 1.114 min [Method A]. MS m/z: 629.5 (M+H). To 0.2 gof this intermediate, in a Parr bottle was added ethyl acetate (15 mL)and 10% Pd/C (0.015 g, 0.014 mmol) under a nitrogen atmosphere. Thevessel was placed on the Parr apparatus and pump/purged three times withnitrogen gas. The vessel was then pressurized to 50 psi with hydrogengas and shaken for 1 hour. The vessel was diluted with 100 mL ofmethanol and the contents was filtered through tightly packed Celite.Upon concentration 0.020 g of the crude residue was purified bypreparative LC-MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with10-mM ammonium acetate; Gradient: 10-50% B over 24 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing theproduct were combined and dried via centrifugal evaporation to afford6-(3-isopropyl-5-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(6.0 mg, 0.0140 mmol); m/z (429.4, M+H). Retention time, 1.262 min usingLCMS Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile: water with 10 mM. ¹H NMR (500 MHz,DMSO-d₆) δ11.12-11.08 (m, 1H), 8.77 (s, 1H), 8.48 (s, 1H), 7.61 (d,J=8.2 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 3.61-3.39 (m, 1H), 2.89 (br t,J=6.9 Hz, 1H), 2.70 (br s, 1H), 2.59 (s, 3H), 2.55 (s, 5H), 2.17 (s,3H), 2.14-2.03 (m, 2H), 1.91-1.75 (m, 6H), 1.68-1.50 (m, 4H), 1.39 (brd, J=6.7 Hz, 6H).

Example 5906-(3-isopropyl-5-((1-methylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial with pressure relief septum was added6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.023 mmol), DMF (1 mL), and DIEA (4.04 μL, 0.023 mmol).Formaldehyde (37% in water) (8.61 μL, 0.116 mmol) was added. Thereaction mixture was stirred at room temperature for 10 minutes. To thereaction mixture was added acetic acid (1.324 μL, 0.023 mmol) and sodiumtriacetoxyborohydride (4.90 mg, 0.023 mmol). The reaction mixture wasstirred at room temperature overnight. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: waterwith 10-mM ammonium acetate; Gradient: 0-100% B over 19 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing theproduct were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 14-39% Bover 25 minutes, then a 2-minute hold at 39% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 435.39 (M+H); Retention Time: 1.17min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 435.43 (M+H); RetentionTime: 0.94 min. Isolated6-(3-isopropyl-5-((1-methylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(5.9 mg, 0.013 mmol, 56.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.30-11.25 (m, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 7.69 (d, J=8.9 Hz, 1H),7.12 (s, 1H), 6.58 (d, J=8.9 Hz, 1H), 4.20-4.14 (m, 2H), 4.04 (s, 1H),3.63-3.51 (m, 1H), 3.30-3.20 (m, 2H), 3.03 (br d, J=11.6 Hz, 2H),2.37-2.28 (m, 4H), 1.81 (br d, J=11.0 Hz, 4H), 1.52-1.46 (m, 6H),1.45-1.35 (m, 2H).

Example 5916-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.023 mmol) was added DMF (0.5 mL), DIEA (0.012 mL, 0.069mmol), and dihydro-2H-pyran-4(3H)-one (2.316 mg, 0.023 mmol). Thereaction mixture was stirred for 5 minutes. Sodium triacetoxyborohydride(14.71 mg, 0.069 mmol) and acetic acid (1.324 μL, 0.023 mmol) wereadded, and the reaction mixture was stirred for 6 hours. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% Bover 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 505.53 (M+H); Retention Time: 1.23min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 505.52 (M+H); RetentionTime: 1 min. Isolated6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(10.8 mg, 0.021 mmol, 89% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.29 (s,1H), 8.59 (s, 1H), 8.50 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.17 (s, 1H),6.57 (d, J=8.5 Hz, 1H), 4.17 (br d, J=6.4 Hz, 2H), 4.07 (s, 3H),3.89-3.82 (m, 2H), 3.29-3.22 (m, 2H), 2.91 (br d, J=10.4 Hz, 2H), 2.09(br t, J=11.1 Hz, 2H), 1.90 (s, 2H), 1.82-1.71 (m, 3H), 1.66 (br d,J=12.5 Hz, 2H), 1.54-1.50 (m, 6H), 1.41 (qd, J=12.0, 4.7 Hz, 2H),1.33-1.21 (m, 2H).

Example 5926-(3-isopropyl-5-(1-isopropylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 20 mL scintillation vial containing6-(5-(azetidin-3-ylmethoxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(15 mg, 0.038 mmol) was added DMF (1 mL) and propan-2-one (2.220 mg,0.038 mmol). The reaction mixture was stirred at room temperature for 10minutes. Acetic acid (2.188 uL, 0.038 mmol) and sodiumtriacetoxyborohydride (24.30 mg, 0.115 mmol) were added and the reactionmixture was stirred at room temperature overnight. A drop of water wasadded, and the crude material was purified via preparative LC/MS withthe following conditions: Column: Xbridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: 10-50% B over 22 minutes, then a 4-minute hold at100% B; Flow: 20 mL/min. Fractions containing the product were combinedand dried via centrifugal evaporation. LC/MS was used to analyze thefinal compound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 435.24 (M+H); RetentionTime: 1.27 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 435.21 (M+H);Retention Time: 1.08 min. Isolated6-(3-isopropyl-5-(1-isopropylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(5.4 mg, 0.012 mmol, 31.5% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.32 (s,1H), 8.57 (s, 1H), 8.50 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.17 (s, 1H),6.57 (d, J=8.5 Hz, 1H), 4.41 (br d, J=6.7 Hz, 2H), 4.06 (s, 3H),3.33-3.19 (m, 3H), 2.98 (br t, J=6.7 Hz, 2H), 2.81-2.70 (m, 1H),2.36-2.25 (m, 1H), 1.56-1.48 (m, 6H), 0.86-0.81 (m, 6H).

Example 5936-(3-isopropyl-5-((1-propylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.024 mmol) was added DMF (500 μL), DIEA (12.39 μL, 0.071mmol), and propionaldehyde (4.12 mg, 0.071 mmol). The reaction mixturewas stirred at room temperature for 5 minutes. Acetic acid (1.353 μL,0.024 mmol) and sodium triacetoxyborohydride (15.03 mg, 0.071 mmol) wereadded to the reaction mixture. The reaction mixture was stirred for 1hour. The crude material was purified via preparative LC/MS with thefollowing conditions: Column: Xbridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate;Gradient: 15-55% B over 19 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the product were combined anddried via centrifugal evaporation. LC/MS was used to analyze the finalcompound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1 mm×50mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 448.94 (M+H); RetentionTime: 1.3 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 449.05 (M+H);Retention Time: 1.05 min. Isolated6-(3-isopropyl-5-(1-propylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(8.6 mg, 0.019 mmol, 79% yield). NMR (500 MHz, DMSO-d₆) δ 11.29 (s, 1H),8.58 (s, 1H), 8.51 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.18 (s, 1H), 6.55(d, J=8.9 Hz, 1H), 5.05-4.93 (m, 1H), 4.08 (s, 3H), 3.31-3.19 (m, 1H),2.77 (br s, 2H), 2.27 (br t, J=7.3 Hz, 2H), 2.19 (br t, J=9.8 Hz, 2H),2.12-2.03 (m, 2H), 1.75-1.64 (m, 2H), 1.51 (s, 6H), 1.48-1.41 (m, 2H),0.86 (t, J=7.2 Hz, 3H).

Example 5946-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (27 mg, 0.044 mmol) was added DMF (0.5 mL), DIEA (0.023 mL, 0.131mmol), and formaldehyde (0.016 mL, 0.218 mmol). The reaction mixture wasstirred for 5 minutes. Acetic acid (2.499 μL, 0.044 mmol) and sodiumtriacetoxyborohydride (27.8 mg, 0.131 mmol) were added. The reactionmixture was stirred for 10 minutes. The material was dissolved in DMF (2mL) and purified via preparative LC/MS with the following conditions:Column: Xbridge C18, 19×200 mm, 5-μrn particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 405.36 (M+H); Retention Time: 1.01min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 405.37 (M+H); RetentionTime: 1.25 min. Isolated6-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine(0.8 mg, 1.879 μmol, 4.3% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.33 (brs, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 7.67-7.61 (m, 2H), 6.53 (d, J=8.7Hz, 1H), 4.99 (br s, 1H), 3.33-3.12 (m, 2H), 2.26-2.11 (m, 5H), 2.06 (brd, J=10.9 Hz, 2H), 1.76 (s, 4H), 1.74-1.65 (m, 2H), 1.54-1.44 (m, 6H).

Example 5956-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(5-(azetidin-3-yloxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(10 mg, 0.026 mmol) was added DMF (1 mL), DIEA (0.014 mL, 0.079 mmol),and tetrahydro-4H-pyran-4-one (2.65 mg, 0.026 mmol). The reactionmixture was stirred for 5 minutes. Acetic acid (1.513 μL, 0.026 mmol)and sodium triacetoxyborohydride (28.0 mg, 0.132 mmol) were added andthe reaction mixture was stirred for 1 hour. The crude material waspurified via preparative LC/MS with the following conditions: Column:Xbridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Xbridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1%trifluoroacetic acid; Gradient: 5-45% B over 20 minutes, then a 4-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the product werecombined and dried via centrifugal evaporation. LC/MS was used toanalyze the final compound. Injection 1 conditions: Column: WatersXbridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results:Observed Mass: 463.0 (M+H); Retention Time: 1.45 min. Injection 2conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 2 results: Observed Mass: 463.4 (M+H); Retention Time: 1.09min. Isolated6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (2.8 mg, 3.95 μmol, 15% yield). ¹H NMR (500 MHz, DMSO-d₆) δ8.82(s, 1H), 8.57 (s, 1H), 8.47 (d, J=8.9 Hz, 1H), 7.21 (d, J=8.9 Hz, 1H),7.16 (s, 1H), 5.71 (br s, 1H), 5.41 (br t, J=10.3 Hz, 1H), 5.10-5.02 (m,1H), 4.13-4.04 (m, 3H), 3.96-3.88 (m, 2H), 3.63-3.52 (m, 1H), 3.65-3.52(m, 2H), 2.00-1.88 (m, 2H), 1.60-1.47 (m, 2H), 1.32 (dd, J=17.1, 7.1 Hz,6H).

Example 5966-(3-isopropyl-5-(1-methylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(5-(azetidin-3-yloxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(10 mg, 0.026 mmol) was added DMF (1 mL), formaldehyde (9.84 μL, 0.132mmol) and DIEA (0.014 mL, 0.079 mmol). The reaction mixture was stirredat room temperature for 30 minutes and acetic acid (1.513 μL, 0.026mmol) and sodium triacetoxyborohydride (28.0 mg, 0.132 mmol) were addedto the reaction mixture. After 10 min, a drop of water was added and thecrude material was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 393.08 (M+H); Retention Time: 1.01min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 393.22 (M+H); RetentionTime: 1 min. Isolated6-(3-isopropyl-5-(1-methylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (1.6 mg, 3,95 μmol, 15% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.38 (br s, 1H), 8.60 (s, 1H), 8.55-8.49 (m, 1H), 7.74-7.67 (m, 1H),7.19 (s, 1H), 6.60 (br d, J=8.5 Hz, 1H), 5.16-5.07 (m, 1H), 4.09 (s,3H), 3.82 (br t, J=6.1 Hz, 1H), 3.32-3.19 (m, 1H), 3.19-3.11 (m, 1H),3.05-2.93 (m, 2H), 2.32 (s, 3H), 1.55-1.48 (m, 6H).

Example 597 1-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo [1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-2-methylpropan-2-ol

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (25 mg, 0.039 mmol) was added MeOH (500 μL), potassium carbonate(10.65 mg, 0.077 mmol), and 2,2-dimethyloxirane (8.34 mg, 0.116 mmol).The vial was sealed and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was filtered andconcentrated under vacuum. The solid material was dissolved in DMF andthe crude material was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-55% Bover 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Conditions:Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results:Observed Mass: 493.58 (M+H); Retention Time: 1.28 min. Isolated1-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-2-methylpropan-2-ol(11 mg, 0.022 mmol, 57.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.33-11.26 (m, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 7.68 (d, J=8.5 Hz, 1H),7.15 (s, 1H), 6.57 (d, J=8.5 Hz, 1H), 4.17 (br d, J=6.1 Hz, 2H),4.08-4.03 (m, 3H), 3.29-3.18 (m, 1H), 2.99 (br d, J=11.0 Hz, 2H), 2.72(s, 2H), 2.26 (s, 2H), 2.17 (br t, J=11.3 Hz, 2H), 1.69 (br d, J=12.2Hz, 2H), 1.54-1.47 (m, 6H), 1.43-1.29 (m, 2H), 1.10-1.04 (m, 6H).

Example 5986-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial with pressure relief septum was added6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.023 mmol), DMF (1 mL), and DIEA (4.04 μL, 0.023 mmol).Acetone (8.49 μL, 0.116 mmol) was added. The reaction mixture wasstirred at room temperature for 10 minutes. Acetic acid (1.324 μL, 0.023mmol) and sodium triacetoxyborohydride (4.90 mg, 0.023 mmol) were added.The reaction mixture was stirred at room temperature overnight. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile PhaseB: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient:5-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min. Fractions containing the product were combined and dried viacentrifugal evaporation. LC/MS was used to analyze the final compound.Injection 1 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, thena 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220nm). Injection 1 results: Observed Mass: 463.26 (M+H); Retention Time:1.46 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 462.98 (M+H); RetentionTime: 1.22 min. Isolated6-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (11.1 mg, 0.016 mmol, 67.4% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.35 (s, 1H), 8.56 (s, 1H), 8.53-8.47 (m, 1H), 7.70 (d, J=8.5 Hz, 1H),7.30 (s, 1H), 6.59 (d, J=8.5 Hz, 1H), 4.22 (d, J=5.8 Hz, 2H), 4.06 (s,3H), 3.45-3.36 (m, 2H), 3.28-3.19 (m, 1H), 3.02-2.84 (m, 3H), 2.14-2.05(m, 1H), 2.02 (br d, J=15.3 Hz, 2H), 1.66-1.54 (m, 2H), 1.51 (d, J=7.0Hz, 6H), 1.24 (d, J=6.4 Hz, 6H).

Example 6006-(3-isopropyl-5-(1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 20 mL vial containing tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (60 mg, 0.099 mmol) was added DCM (500 μl)and TFA (500 μl). The reaction mixture was stirred at rt for 3 hours.The reaction mixture was concentrated under a stream of nitrogen anddried under vacuum. To the reaction mixture was added DMF (1 mL), DIEA(17.27 μl, 0.099 mmol), formaldehyde (37% in water) (36.8 μL, 0.494mmol), and acetic acid (5.66 μl, 0.099 mmol). The reaction mixture wasstirred for 5 minutes. Sodium triacetoxyborohydride (62.9 mg, 0.297mmol) was added and the reaction mixture was stirred at rt for 1 hour. Adrop of water was added and the crude material was purified viapreparative LC/MS with the following conditions: Column: Xbridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing theproduct were combined and dried via centrifugal evaporation. LC/MS wasused to analyze the final compound. Injection 1 conditions: Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100%B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Injection 2 conditions:Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.Isolated6-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(25.9 mg, 0.060 mmol, 61.0% yield). LC MS rt=0.971 (m+1=421)[QC-ACN-TFA-XB]. 1H NMR (500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 8.58 (s,1H), 8.51 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.18 (s, 1H), 6.55 (d, J=8.5Hz, 1H), 5.00 (br s, 1H), 4.08 (s, 3H), 3.32-3.11 (m, 1H), 2.70 (br s,1H), 2.57-2.54 (m, 1H), 2.20 (s, 3H), 2.07 (br s, 2H), 1.91 (br s, 2H),1.72 (br d, J=9.8 Hz, 2H), 1.52 (br d, J=6.7 Hz, 6H).

Example 6016-(3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 601A: tert-butyl5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a 100 mL round-bottom flask cooled to 0° C. was added5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine (1.33 g) [materialsynthesized similarly as above for Intermediate 1B] THF (10 mL), TEA(1.428 mL, 10.25 mmol), and DMAP (0.083 g, 0.683 mmol). BOC-anhydride(1.745 mL, 7.52 mmol) was added slowly over 10 minutes and the reactionstirred for 30 minutes. The reaction was concentrated under vacuum togive an oil. The oil was purified by column chromatography on a TeledyneIsco instrument (24 g Silica, 100% Hexanes-80% EtOAc/Hexanes). Likefractions were combined and concentrated under vacuum to give a slightyellow oil, tert-butyl5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.06 g).LC MS rt=1.20 min. (m+1=295) [B1]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d,J=8.7 Hz, 1H), 7.71 (s, 1H), 7.38 (d, J=8.7 Hz, 1H), 3.22-3.08 (m, 1H),1.62 (s, 9H), 1.31 (d, J=6.8 Hz, 6H).

Intermediate 601B: tert-butyl5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-1H-pyrrolo[3,2-b] pyridine-1-carboxylate

A 1 dram vial containing tert-butyl 4-hydroxypiperidine-1-carboxylate(137 mg, 0.678 mmol), cesium carbonate (166 mg, 0.509 mmol), toluene (1mL), andmethanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(8.53 mg, 10.18 μmol) under a nitrogen atmosphere was heated to 90° C.for 3 minutes. tert-butyl5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (100 mg,0.339 mmol) is added to the reaction and heated overnight at 90° C. Thetemperature was increased to 110° C. for 4 hours. The reaction wasfiltered through a pad of Celite and concentrated under vacuum. Theresulting oil was purified by column chromatography on a Teledyne Iscoinstrument (24 g Silica, 100% Hexanes-100% EtOAc). Like fractions werecombined and concentrated under vacuum to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(37 mg, 0.081 mmol, 24% yield). LC MS rt=1.33 min. (m+1=460) [B1].

Intermediate 601C: tert-butyl5-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A 1 dram vial containing tert-butyl3-(hydroxymethyl)azetidine-1-carboxylate (60.7 mg, 0.324 mmol), cesiumcarbonate (158 mg, 0.486 mmol), toluene (2 mL), andmethanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(8.16 mg, 9.73 μmol) under a nitrogen atmosphere was heated to 105° C.for 5 minutes. tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (110 mg,0.324 mmol) in toluene (1 mL) was added to the reaction and heatedovernight at 105° C. The reaction was diluted with water (10 mL) andextracted with EtOAc (3×10 mL). The organic layers were combined andpassed over a pad of Celite and concentrated under vacuum to give clearoil. Purified by column chromatography on a Teledyne Isco instrument (24g Silica, 100% Hexanes-50% EtOAc/hexanes). Like fractions were combinedand concentrated under vacuum to give tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(107 mg, 0.228 mmol, 70.4% yield). LC MS rt=1.26 min. (m+1=446) [B1]. ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.27-8.09 (m, 1H), 7.44 (br. s., 1H), 6.64(d, J=8.9 Hz, 1H), 4.51 (d, J=6.7 Hz, 2H), 4.08 (t, J=8.6 Hz, 2H), 3.85(dd, J=8.7, 5.4 Hz, 2H), 3.21 (dt, J=13.2, 6.7 Hz, 1H), 3.02 (dquin,J=13.6, 6.8 Hz, 1H), 1.67 (s, 9H), 1.46 (s, 9H), 1.38 (d, J=7.0 Hz, 6H).

Intermediate 601D: tert-butyl5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A 1 dram vial containing tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (337 mg, 1.565 mmol), cesiumcarbonate (765 mg, 2.348 mmol), toluene (5 mL), andmethanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(39.4 mg, 0.047 mmol) under a nitrogen atmosphere was heated to 105° C.for 5 minutes. tert-Butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (531 mg,1.565 mmol) in toluene (1 mL) was added to the reaction and heated for 3hours at 105° C. The reaction was diluted with water (10 mL) andextracted with EtOAc (3×10 mL). The organic layers were combined andpassed over a pad of Celite and concentrated under vacuum to give aclear oil. Purified by column chromatography on a Teledyne Iscoinstrument (24 g Silica, 100% Hexanes-50% EtOAc/hexanes). Like fractionswere combined and concentrated under vacuum to give tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(408 mg, 0.861 mmol, 55.0% yield). LC MS rt=1.33 min (m+1=474) [B1]. ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.26-8.00 (m, 1H), 7.50-7.33 (m, 1H),6.67-6.57 (m, 1H), 4.24 (d, J=6.5 Hz, 2H), 4.21-4.02 (m, 2H), 3.26-3.14(m, 1H), 2.64 (br d, J=7.5 Hz, 2H), 2.10-1.92 (m, 1H), 1.87-1.79 (m,2H), 1.74-1.61 (m, 9H), 1.49-1.44 (m, 9H), 1.38 (d, J=6.8 Hz, 6H),1.33-1.22 (m, 2H).

Intermediate 601E: tert-butyl3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A 1 dram vial containing methanol (0.918 mL, 22.70 mmol), cesiumcarbonate (1109 mg, 3.40 mmol), toluene (5 mL), andmethanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(38.1 mg, 0.045 mmol) under a nitrogen atmosphere was heated to 105° C.for 5 minutes. tert-Butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (770 mg,2.270 mmol) in toluene was added to the reaction and heated at 105° C.After 30 minutes, the reaction was diluted with water (10 mL) andextracted with EtOAc (3×10 mL). The organic layers were combined andpassed over a pad of Celite and concentrated under vacuum to give aclear oil. Purified by column chromatography on a Teledyne Iscoinstrument (24 g Silica, 100% Hexanes-50% EtOAc/hexanes). Like fractionswere combined and concentrated under vacuum to give tert-butyl3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (48 mg,0.165 mmol, 7.3% yield. LC MS rt=1.22 min. (m+1=291) [B1].

Intermediate 601F: tert-butyl3-isopropyl-5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a nitrogen flushed 20 mL vial with a pressure relief septum was addedtert-butyl 3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(70 mg, 0.241 mmol), THF (2 mL), and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.054 mL, 0.265mmol). The vial was cooled to −40° C. in a dry ice/NMP bath. LDA (0.301mL, 0.603 mmol) was added dropwise over 15 minutes. The reaction waswarmed to 0° C. The reaction was cooled to −40° C. and quenched withsaturated KHSO₄. The reaction was warmed to room temperature, dilutedwith water (10 mL) and extracted with EtOAc (3×10 mL). Organic layerswere combined, dried over sodium sulfate, filtered, and concentratedunder vacuum to give a clear oil. The clear oil was purified by columnchromatography on a Teledyne Isco instrument (12 g Silica, 100%Hexanes-50% EtOAc/Hexanes). Like fractions were combined andconcentrated under vacuum to give tert-butyl3-isopropyl-5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(50 mg, 0.120 mmol, 49.8% yield). LC MS rt=1.34 min. (m+1=417) [B1].

Example 601

To a 2 dram vial with pressure relief septum was added tert-butyl3-isopropyl-5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(50 mg, 0.120 mmol), 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(27.4 mg, 0.120 mmol), 2^(nd) generation Xphos precatalyst (4.72 mg,6.00 μmol), and THF (1 mL). The reaction was evacuated and flushed withnitrogen several times. Aqueous tripotassium phosphate (3 M, 0.040 mL,0.120 mmol) was added and the vial was evacuated and flushed withnitrogen several times. The reaction was heated at 65° C. for 1 hour.The reaction mixture was diluted with brine (1 mL) and extracted withEtOAc (3×2 mL). The organic layers were combined, dried over sodiumsulfate, filtered, and dried under vacuum. The resulting oil waspurified by column chromatography on a Teledyne Isco instrument (12 gSilica, 100% hexanes-100% EtOAc). Like fractions were combined andconcentrated under vacuum. The resulting oil was treated with 1:1TFA:DCM for 30 minutes, then concentrated under a stream of nitrogen.The resulting oil was neutralized with sodium bicarbonate and extractedwith EtOAc. The organic layer was dried over sodium sulfate, filteredand concentrated to give a solid,6-(3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(11.4 mg, 0.032 mmol, 26.7% yield). LC MS rt=0.77 min. (m+1=338) [B1].¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 8.60 (d, J=1.2 Hz, 1H), 8.52(s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.19 (d, 1=1.1 Hz, 1H), 6.59 (d, J=8.7Hz, 1H), 4.08 (s, 3H), 4.06-3.98 (m, 1H), 3.89 (s, 3H), 1.57-1.52 (m,6H).

Example 6022-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-N,N-dimethylacetamide

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.023 mmol) was added DMF (1 mL), DIEA (0.012 mL, 0.069mmol), and 2-chloro-N,N-dimethylacetamide (4.22 mg, 0.035 mmol). Thereaction mixture was stirred at room temperature overnight. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-55% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 506.1 (M+H); Retention Time: 1.28min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 506.25 (M+H); RetentionTime: 1.01 min. Isolated2-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-N,N-dimethylacetamide(4.2 mg, 8.06 μmol, 34.8% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.30 (s,1H), 8.59 (s, 1H), 8.50 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.18 (s, 1H),6.57 (d, J=8.5 Hz, 1H), 4.18 (d, J=6.1 Hz, 2H), 4.07 (s, 3H), 3.29-3.20(m, 1H), 3.09 (s, 2H), 3.02 (s, 3H), 2.88-2.82 (m, 2H), 2.80 (s, 3H),2.00 (br t, J=10.7 Hz, 2H), 1.86-1.76 (m, 1H), 1.73 (br d, J=12.2 Hz,2H), 1.53 (br d, J=1.0 Hz, 6H), 1.37-1.25 (m, 2H).

Example 6036-(3-isopropyl-5-((1-isopropylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 2 dram vial containing tert-butyl5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(31 mg, 0.051 mmol) was added DCM (1 mL) and TFA (1 mL). The reactionmixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated under a stream of nitrogen and dried undervacuum. To the resulting oil was added DMF (1 mL), DIEA (0.027 mL, 0.153mmol), and acetone (0.019 mL, 0.255 mmol). The reaction mixture wasstirred at room temperature for 30 minutes. Sodium triacetoxyborohydride(54.1 mg, 0.255 mmol) and acetic acid (2.93 μL, 0.051 mmol) were added,and the reaction mixture was stirred at room temperature overnight. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile PhaseB: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient:5-45% B over 27 minutes, then a 3-minute hold at 100% B; Flow: 20mL/min. Fractions containing the product were combined and dried viacentrifugal evaporation. The yield of the product was 4.5 mg. LC/MS wasused to analyze the final compound. Injection 1 conditions: Column:Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results:Observed Mass: 449 (M+H); Retention Time: 1.22 min. Injection 2conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 2 results: Observed Mass: 449.29 (M+H); Retention Time: 1.07min.

Example 6046-(3-isopropyl-5-((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.023 mmol) was added DMF (0.75 mL), DIEA (4.04 μL, 0.023mmol), and 1-bromo-2-(methylsulfonyl)ethane (4.33 mg, 0.023 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was heated to 70° C. for 3 hours. The crude material waspurified via preparative LC/MS with the following conditions: Column:Xbridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 527.45 (M+H); Retention Time: 1.5min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 527.47 (M+H); RetentionTime: 0.98 min. Isolated6-(3-isopropyl-5-((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(3.8 mg, 7.00 μmol, 30.3% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.29 (s,1H), 8.58 (s, 1H), 8.50 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.17 (s, 1H),6.57 (d, J=8.9 Hz, 1H), 4.18 (br d, J=6.4 Hz, 2H), 4.07 (s, 3H), 3.89(s, 1H), 3.29-3.20 (m, 2H), 3.02 (s, 3H), 2.92 (br d, J=11.0 Hz, 2H),2.68 (t, J=6.7 Hz, 2H), 1.95 (br t, J=10.8 Hz, 2H), 1.87-1.79 (m, 1H),1.78-1.72 (m, 2H), 1.55-1.49 (m, 6H), 1.37-1.24 (m, 2H).

Examples 605 and 6114(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dipropylcyclohexan-1-amine

To a 1 dram vial containing4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)cyclohexan-1-amine,2 TFA (15 mg, 0.023 mmol) was added DCM (1 mL), DMF (0.5 mL), DIEA (8.08μl, 0.046 mmol), and propionaldehyde (3.32 μL, 0.046 mmol). The reactionmixture was stirred at room temperature for 30 minutes. Acetic acid(1.324 μL, 0.023 mmol) and sodium triacetoxyborohydride (14.71 mg, 0.069mmol) were added to the reaction mixture. The reaction mixture wasstirred for 3 hours. A drop of water and DMF (1 mL) were added, and thenthe crude material was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 22-62% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation to afford two compounds: Isolate 1 and Isolate 2. Thesecompounds were cis and trans isomers, but the identities of isomers inthe isolates were not assigned.

Example 605: Isolate 1:4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dipropylcyclohexan-1-amine(9.9 mg, 0.020 mmol, 85% yield). LC/MS was used to analyze the finalcompound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1 mm×50mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 505.48 (M+H); RetentionTime: 1.51 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 505.46 (M+H);Retention Time: 1.24 min. ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H),8.58 (s, 1H), 8.50 (s, 1H), 7.68-7.60 (m, 1H), 7.18 (s, 1H), 6.50 (d,J=8.9 Hz, 1H), 4.86 (br s, 1H), 4.27 (q, J=7.0 Hz, 1H), 4.07 (s, 2H),3.25 (br dd, J=10.2, 6.0 Hz, 1H), 3.19-3.10 (m, 1H), 2.89 (s, 1H),2.70-2.67 (m, 1H), 2.73 (s, 1H), 2.47-2.33 (m, 3H), 2.26 (br s, 1H),1.79 (br s, 1H), 1.53 (br d, J=6.7 Hz, 6H), 1.44-1.33 (m, 6H), 1.32-1.20(m, 1H), 0.99 (d, J=6.4 Hz, 3H), 0.84 (t, J=7.3 Hz, 4H).

Example 611: Isolate 2:4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dipropylcyclohexan-1-amine(4.2 mg, 7.91 μmol, 34.2% yield). LC/MS was used to analyze the finalcompound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1 mm×50mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 505.46 (M+H); RetentionTime: 1.57 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 505.46 (M+H);Retention Time: 1.3 min. ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.58(s, 1H), 8.50 (s, 1H), 7.94 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.17 (s,1H), 6.58 (d, J=8.5 Hz, 1H), 5.20 (br s, 1H), 4.07 (s, 3H), 3.29-3.22(m, 1H), 3.19-3.11 (m, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 2.46-2.34 (m,2H), 2.13 (br s, 1H), 1.76 (br s, 1H), 1.60 (br d, J=8.9 Hz, 3H), 1.51(br d, J=6.7 Hz, 5H), 1.42-1.35 (m, 4H), 0.99 (d, J=6.1 Hz, 3H), 0.84(t, J=7.2 Hz, 6H).

Example 6066-(3-isopropyl-5-(1-propylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.023 mmol) was added DMF (0.5 mL), DIEA (0.012 mL, 0.069mmol), propionaldehyde (6.72 mg, 0.116 mmol). The reaction mixture wasstirred for 5 minutes. Sodium triacetoxyborohydride (14.71 mg, 0.069mmol) and acetic acid (1.324 μL, 0.023 mmol) were added and the reactionwas stirred at room temperature for 6 hours. One drop of water wasadded, and the crude material was purified via preparative LC/MS withthe following conditions: Column: Xbridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: 10-50% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the product were combinedand dried via centrifugal evaporation. LC/MS was used to analyze thefinal compound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 462.94 (M+H); RetentionTime: 1.51 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 463.3 (M+H);Retention Time: 1.25 min. Isolated6-(3-isopropyl-5-(1-propylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(8.6 mg, 0.019 mmol, 80% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.33-11.26(m, 1H), 8.62-8.55 (m, 1H), 8.53-8.47 (m, 1H), 7.71-7.63 (m, 1H), 7.18(s, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.21-4.16 (m, 2H), 4.08 (s, 3H),3.30-3.19 (m, 1H), 2.89 (br d, J=10.7 Hz, 2H), 2.23 (br t, J=7.3 Hz,2H), 1.93-1.80 (m, 3H), 1.75 (br d, J=12.2 Hz, 2H), 1.52 (br d, J=7.0Hz, 6H), 1.44 (dq, J=14.5, 7.4 Hz, 2H), 1.38-1.26 (m, 2H), 0.84 (t,J=7.5 Hz, 3H).

Example 6076-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.024 mmol) is added DMF (500 μL), DIEA (12.39 μL, 0.071mmol), and dihydro-2H-pyran-4(3H)-one (2.367 mg, 0.024 mmol). Thereaction mixture was stirred at room temperature for 5 minutes. Aceticacid (1.353 μL, 0.024 mmol) and sodium triacetoxyborohydride (15.03 mg,0.071 mmol) were added to the reaction. The reaction mixture was stirredovernight. The crude material was purified via preparative LC/MS withthe following conditions: Column: Xbridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: 10-50% B over 20 minutes, then a 4-minute hold at100% B; Flow: 20 mL/min. Fractions containing the product were combinedand dried via centrifugal evaporation. The material was further purifiedvia preparative LC/MS with the following conditions: Column: XbridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: waterwith 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a3-minute hold at 100% B; Flow: 20 mL/min. Fractions containing theproduct were combined and dried via centrifugal evaporation. LC/MS wasused to analyze the final compound. Injection 1 conditions: Column:Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection) results:Observed Mass: 491.21 (M+H); Retention Time: 1.33 min. Injection 2conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and IJV (220 nm).Injection 2 results: Observed Mass: 491.16 (M+H); Retention Time: 1.07min. Isolated6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(6.7 mg, 0.013 mmol, 56% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s,1H), 8.57 (s, 1H), 8.50 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.16 (s, 1H),6.54 (d, J=8.5 Hz, 1H), 5.03-4.93 (m, 1H), 4.11-4.03 (m, 3H), 3.88 (brd, J=7.6 Hz, 2H), 3.32-3.21 (m, 3H), 2.86 (br d, J=10.4 Hz, 2H),2.41-2.32 (m, 2H), 2.13-2.03 (m, 2H), 1.94-1.86 (m, 1H), 1.73-1.61 (m,4H), 1.51 (br d, J=7.0 Hz, 6H), 1.48-1.36 (m, 2H).

Example 6086-(3-isopropyl-5-(1-methylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To a 20 mL scintillation vial containing tert-butyl5-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(40 mg, 0.067 mmol) was added DCM (500 mL) and TFA (500 mL). Thereaction mixture was stirred at room temperature for 3 hours,concentrated under a stream of nitrogen and dried under vacuum. Theresulting oil was dissolved in DMF (1 mL) and DIEA (0.035 mL, 0.202mmol) and formaldehyde (37% in water) (0.025 mL, 0.337 mmol) were added.The reaction mixture was stirred at room temperature for 10 minutes.Acetic acid (3.86 μL, 0.067 mmol) and sodium triacetoxyborohydride (42.9mg, 0.202 mmol) were added and the reaction mixture was stirred at roomtemperature overnight. The crude material was purified via preparativeLC/MS with the following conditions: Column: Xbridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mMammonium acetate; Gradient: 10-50% B over 19 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:Xbridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 8-33% Bover 25 minutes, then a 2-minute hold at 33% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 407.34 (M+H); Retention Time: 0.96min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 406.93 (M+H); RetentionTime: 1.11 min. Isolated6-(3-isopropyl-5-(1-methylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (1.7 mg, 2.63 μmol, 3.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.47-11.38 (m, 1H), 8.61 (s, 1H), 8.53 (s, 1H), 7.74 (d, J=8.7 Hz, 1H),7.19 (s, 1H), 6.68 (dd, J=8.5, 5.9 Hz, 1H), 4.54-4.40 (m, 2H), 4.08 (s,3H), 3.99-3.90 (m, 1H), 3.60-3.50 (m, 1H), 3.49-3.42 (m, 1H), 3.29-3.23(m, 2H), 2.90-2.81 (m, 3H), 2.73 (s, 1H), 1.54 (br d, J=5.6 Hz, 6H).

Example 6092-(4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-N,N-dimethylacetamide

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (20 mg, 0.032 mmol) was added DMF (1 mL), DIEA (0.017 mL, 0.095mmol), and 2-chloro-N,N-dimethylacetamide (11.50 mg, 0.095 mmol). Thereaction mixture was stirred at room temperature overnight. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 492.13 (M+H); Retention Time: 1.25min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 492.01 (M+H); RetentionTime: 1.28 min. Isolated2-(4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-N,N-dimethylacetamide(11.2 mg, 0.023 mmol, 71.6% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.30(s, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.19 (s,1H), 6.55 (d, J=8.5 Hz, 1H), 5.04-4.96 (m, 1H), 4.08 (s, 3H), 3.32-3.22(m, 1H), 3.18 (s, 2H), 3.04 (s, 2H), 2.89-2.73 (m, 4H), 2.36 (br t,J=9.3 Hz, 2H), 2.12-2.05 (m, 2H), 1.90 (br s, 1H), 1.74-1.64 (m, 2H),1.56-1.48 (m, 6H), 1.24 (s, 1H).

Examples 610 and 6144(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dimethylcyclohexan-1-amine

To a 1 dram vial containing4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)cyclohexan-1-amine,2 TFA (15 mg, 0.023 mmol) was added DMF (0.5 mL), DCM (1 mL), DIEA (8.08μL, 0.046 mmol), and formaldehyde (1.911 μL, 0.069 mmol). The reactionmixture was stirred at room temperature for 30 minutes. Acetic acid(1.324 μL, 0.023 mmol) and sodium triacetoxyborohydride (14.71 mg, 0.069mmol) were added and the reaction mixture was stirred at roomtemperature for 1 hour. The crude material was purified via preparativeLC/MS with the following conditions: Column: Xbridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1%trifluoroacetic acid; Gradient: 5-50% B over 20 minutes, then a 6-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the product werecombined and dried via centrifugal evaporation to afford two compounds:Isolate 1 and Isolate 2. These compounds are cis and trans isomers, butthe identities of the isomers in the isolates were not assigned.

Example 610: Isolate 1:4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dimethylcyclohexan-1-amine,2 TFA (8.5 mg, 0.012 mmol, 53.2% yield). LC/MS was used to analyze thefinal compound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 449.37 (M+H); RetentionTime: 1.11 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 449.36 (M+H);Retention Time: 0.91 min. 1H NMR (500 MHz, DMSO-d₆) δ11.36 (s, 1H), 8.59(s, 1H), 8.52 (s, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.17 (s, 1H), 6.54 (d,J=8.5 Hz, 1H), 4.96-4.86 (m, 1H), 4.12-4.04 (m, 3H), 3.31-3.20 (m, 2H),2.38 (br d, J=11.6 Hz, 2H), 2.18-2.07 (m, 2H), 1.73-1.58 (m, 3H),1.55-1.38 (m, 11H).

Example 614: Isolate 2:4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dimethylcyclohexan-1-amine,2 TFA (3.1 mg, 4.44 μmol, 19% yield). LC/MS was used to analyze thefinal compound. Injection 1 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 1 results: Observed Mass: 449.38 (M+H); RetentionTime: 1.26 min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm). Injection 2 results: Observed Mass: 449.38 (M+H);Retention Time: 0.99 min. ¹H NMR (500 MHz, DMSO-d₆) δ11.39-11.32 (m,1H), 8.61-8.56 (m, 1H), 8.52 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.17 (s,1H), 6.60 (d, J=8.9 Hz, 1H), 5.25 (br s, 1H), 4.08 (s, 3H), 3.31-3.23(m, 2H), 2.25 (br d, J=10.7 Hz, 2H), 1.95-1.84 (m, 2H), 1.81-1.66 (m,4H), 1.55-1.47 (m, 6H).

Example 6126-(3-isopropyl-5-(1-isopropylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxyl-[1,2,4]triazolo[1,5-a]pyridine

To a 1 dram vial containing6-(5-(azetidin-3-yloxy)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(10 mg, 0.026 mmol) was added DMF (1 mL), DIEA (0.014 mL, 0.079 mmol),and propan-2-one (1.535 mg, 0.026 mmol). The reaction mixture wasstirred at room temperature for 30 minutes. Acetic acid (1.513 μL, 0.026mmol) and sodium triacetoxyborohydride (28.0 mg, 0.132 mmol) were addedand the reaction mixture was stirred at room temperature overnight. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Xbridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-55% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm).Injection 1 results: Observed Mass: 421.04 (M+H); Retention Time: 1.4min. Injection 2 conditions: Column: Waters Xbridge C18, 2.1 mm×50 mm,1.7 particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). Injection 2 results: Observed Mass: 420.96 (M+H); RetentionTime: 1.17 min. Isolated6-(3-isopropyl-54(1-isopropylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(5.2 mg, 0.012 mmol, 44.9% yield).

Example 6131-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-2-methylpropan-2-ol

To a 1 dram vial containing6-(3-isopropyl-5-(piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine,2 TFA (15 mg, 0.024 mmol) was added MeOH (500 μL), potassium carbonate(9.80 mg, 0.071 mmol), and 2,2-dimethyloxirane (1.705 mg, 0.024 mmol).The reaction mixture was stirred at rt overnight then filtered andconcentrated under vacuum. The crude material was dissolved in DMF andpurified via preparative LC/MS with the following conditions: Column:Xbridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-55% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the product were combined and dried via centrifugalevaporation. LC/MS was used to analyze the final compound. Injection 1conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.Injection 2 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection:UV at 220 nm. Isolated1-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3;2-b]pyridin-5-yl)oxy)piperidin-1-yl)-2-methylpropan-2-ol(9.8 mg, 0.019 mmol, 81% yield). LCMS retention time 1.20 min, m/z=479.2(M+H) [QC-ACN-AA-XB]. 1H NMR (500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 8.59(s, 1H), 8.51 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.18 (s, 1H), 6.55 (d,J=8.9 Hz, 1H), 4.98 (br s, 1H), 4.08 (s, 3H), 3.25 (dt, J=13.6, 6.6 Hz,1H), 2.91 (br d, J=11.0 Hz, 2H), 2.38 (br t, J=9.2 Hz, 2H), 2.06 (br d,J=10.7 Hz, 2H), 1.79-1.62 (m, 2H), 1.57-1.46 (m, 6H), 1.23 (s, 3H), 1.10(s, 6H).

Example 6496-(5-(azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 649A: tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A suspension of tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (150 mg,0.442 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (209 mg, 0.884mmol), tris(trimethylsilyl)silane (165 mg, 0.663 mmol),[Ir(dF(CF₃)ppy)₂(dtbbpy)]PF₆ (1.24 mg, 1.11 μmol), and Na₂CO₃ (187 mg,1.77 mmol) in 1,4-dioxane (3.5 mL) in a vial with a pressure-reliefseptum-lined cap and a stir bar was degassed with nitrogen gas for 5minutes. To a separate vial was added nickel(II) chloride ethyleneglycol dimethyl ether complex (7.29 mg, 0.033 mmol) and4,4′-di-tert-butyl-2,2′-bipyridine (10.7 mg, 0.040 mmol), which wasevacuated and backfilled with nitrogen gas followed by 1,4-dioxane (0.88mL). This mixture was degassed with nitrogen gas for 10 minutes andstirred. The resulting solution containing the nickel complex was addedto the suspension containing all other reagents, and then the resultingmixture was further degassed with nitrogen gas for another 10 minutes.The vessel was then sealed and placed in a rack with stirring andirradiation with 34 W Kessil KSH 150B blue grow lamps and a cooling fanfor 17 hours. Upon completion, the reaction mixture was diluted withDCM, filtered, and concentrated. The crude material was taken up inhexanes with a trace of DCM for solubility and purified by silica gelcolumn chromatography on a Teledyne Isco instrument eluting with Hex/DCM0-100%, then Hex/EtOAc 0-50% to afford tert-butyl5-(1-(tert-butoxycarbonypazetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (100 mg, 0.241 mmol, 54.4% yield). LCMS retention time 1.04 [TS].MS (E⁺) m/z: 416.3 (M+H). This reaction was repeated several times toobtain larger quantities of material.

Intermediate 649B: tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A solution containing tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(456 mg, 1.10 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (448 μL, 2.195mmol) in dry THF (5.5 mL) under a nitrogen atmosphere was cooled in adry ice/acetone bath to −78° C. and treated with LDA (2M in THF, 2.75mL, 5.50 mmol). The mixture was allowed to warm to −30° C. over 30 minand stirred at −30° C. for 30 min. The reaction was then quenched withsaturated aqueous NH₄Cl solution, water, and DCM. The organic layer wasseparated, dried over sodium sulfate, filtered and concentrated. Thecrude material was combined with the crude material from a similarexperiment following the same procedure using 100 mg (0.241 mmol) ofstarting material tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.The combined crude materials were purified by silica gel columnchromatography on a Teledyne Isco instrument loading in hexanes andeluting with Hex/EtOAc 0-50% to afford tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(340 mg) combined from both experiments. LCMS retention time 1.18 [TS].MS (E⁺) m/z: 542.3 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 7.96 (d,J=8.4 Hz, 1H), 7.03 (d, J-8.5 Hz, 1H), 4.34-4.27 (m, 2H), 4.27-4.22 (m,2H), 3.99-3.89 (m, 1H), 3.37-3.26 (m, 1H), 1.66 (s, 9H), 1.47 (s, 9H),1.48 (br d, J=7.0 Hz, 6H), 1.44 (s, 12H).

Intermediate 649C: tert-butyl3-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidine-1-carboxylate

In a reaction vial with a pressure-relief septum-lined cap and stir bar,neat tert-butyl5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(340 mg, 0.628 mmol) under a nitrogen atmosphere was heated to 160° C.with slow stirring for 45 minutes. Upon completion, the material wasdissolved in DCM and concentrated to afford tert-butyl3-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidine-1-carboxylateas an off-white foam considered to be quantitative yield. Carriedforward as is. Note: material converted to the free boronic acid on LCMSand was observed as such, although NMR indicated that the product waspurely the compound. LCMS retention time (boronic acid) 0.67 [TS]. MS(E⁺) m/z: 360.2 (M+H, boronic acid). ¹H NMR (499 MHz, CHLOROFORM-d) δ8.23 (br s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H),4.36-4.24 (m, 4H), 4.01-3.92 (m, 1H), 3.73 (spt, J=7.0 Hz, 1H), 1.53 (d,J=7.0 Hz, 6H), 1.48 (s, 9H), 1.36 (s, 12H).

Intermediate 649D: tert-butyl3-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidine-1-carboxylate

To a mixture of tert-butyl3-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidine-1-carboxylate(138 mg, 0.313 mmol),6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (78 mg, 0.344 mmol),and 2^(nd) generation Xphos precatalyst (12.3 mg, 0.016 mmol) in1,4-dioxanc (2.1 mL) was added aqueous K₃PO₄ (3M, 0.31 mL, 0.93 mmol)and the biphasic mixture was degassed with nitrogen gas for 10 min. Thereaction vial was sealed and stirred at 65° C. for 1.5 hours. Uponcompletion, the reaction mixture was cooled to room temperature andconcentrated. The crude material was suspended in DCM and purified bysilica gel column chromatography on a Teledyne Isco instrument elutingwith Hex/EtOAc 0-100% to afford tert-butyl3-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidine-1-carboxylate(111 mg, 0.241 mmol, 77% yield). LCMS retention time 0.72 [TS]. MS (E⁺)m/z: 461.3 (M+H).

Example 649

To a solution of tert-butyl3-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)azetidine-1-carboxylate(111 mg, 0.241 mmol) in DCM (4.8 mL) at room temperature was added 4MHCl in 1,4-dioxane (1.2 mL, 4.80 mmol). The reaction mixture was stirredat room temperature for 5 minutes. Upon completion, the reaction mixturewas concentrated to afford6-(5-(azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,HCl (0.241 mmol) in recovery considered to be quantitative. The majorityof this material was carried forward as is. An aliquot of this material(approximated to be 0.012 mmol) was purified via preparative LC/MS withthe following conditions: Column: Xbridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: 5-90% B over 20 minutes, then a 4-minute hold at 100%B; Flow: 20 mL/min. The fractions containing the product were combinedand dried via centrifugal evaporation to afford6-(5-(azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(2.5 mg, 6.80 μmop. LCMS retention time 0.69 [QC-ACN-TFA-XB]. MS (E⁺)m/z: 361.3 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.47 (s,1H), 7.65 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 4.18-4.09 (m, 1H),4.09-3.96 (m, 2H), 3.91-3.80 (m, 2H), 2.96-2.87 (m, 1H), 2.59 (s, 3H),2.16 (s, 3H), 1.42 (br d, J=6.7 Hz, 6H).

Example 6536-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)azetidin-3-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of6-(5-(azetidin-3-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,HCl (18.26 mg, 0.046 mmol) in DMF (1 mL) was added Et₃N (0.032 mL, 0.230mmol) and 1-bromo-2-(methylsulfonyl)ethane (12.9 mg, 0.069 mmol). Theresulting solution was stirred for 90 minutes at room temperature, andthen another aliquot of 1-bromo-2-(methylsulfonyl)ethane (12.9 mg, 0.069mmol) was added. The reaction mixture was stirred for 60 minutes moreand then diluted with a few drops of water, DMF, and purified viapreparative LC/MS with the following conditions: Column: Xbridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with10-mM ammonium acetate; Gradient: 10-100% B over 20 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min. The fractions containing theproduct were combined and dried via centrifugal evaporation to afford6-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)azetidin-3-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(15.7 mg, 0.033 mmol, 71.7% yield). LCMS retention time 0.8 min[QC-ACN-TFA-XB]. MS (E⁺) m/z: 467.4 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ11.17 (s, 1H), 8.76 (s, 1H), 8.46 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.08(d, J=8.2 Hz, 1H), 3.83 (quin, J=7.6 Hz, 1H), 3.75-3.69 (m, 2H), 3.38(t, J=7.2 Hz, 2H), 3.20-3.12 (m, 2H), 3.05 (s, 3H), 2.93-2.83 (m, 3H),2.58 (s, 3H), 2.15 (s, 3H), 1.40 (br d, J=7.0 Hz, 6H).

Example 6604-isopropyl-2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine

2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine,TFA (22.99 mg, 0.0454 mmol) and Et₃N (0.05 mL, 0.359 mmol) were mixed inDMF (0.454 mL). Acetone (0.018 mL, 0.245 mmol) was added to the reactionvial followed by sodium triacetoxyborohydride (28.9 mg, 0.136 mmol) andthe reaction mixture was stirred for 17 hours at room temperature. Atthis time, another aliquot of acetone (0.018 mL, 0.245 mmol) and sodiumtriacetoxyborohydride (28.9 mg, 0.136 mmol) were each added. Thereaction mixture was stirred for 7 hours more at room temperature. Thereaction was quenched by the addition of water, 1.5 M aqueous K₂HPO₄solution, and DCM. The organic layer was separated, concentrated, anddiluted with DMSO. The material was purified via preparative LC/MS withthe following conditions: Column: Xbridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 11% B, 11-51% B over 20 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS and UVsignals. Fractions containing the product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Xbridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: waterwith 0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 12% B,12-35% B over 25 minutes, then a 2-minute hold at 100% B; Flow Rate: 20mL/min; Column Temperature: 25° C. Fraction collection was triggered byUV signals. Fractions containing the product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Xbridge C18,200 mm×30 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: waterwith 10-mM ammonium acetate; Gradient: a 0-minute hold at 10% B, 10-50%B over 20 minutes, then a 2-minute hold at 100% B; Flow Rate: 45 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MS andUV signals. Fractions containing the product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Xbridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: waterwith 0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 11% B,11-35% B over 25 minutes, then a 2-minute hold at 100% B; Flow Rate: 20mL/min; Column Temperature: 25° C. Fraction collection was triggered byUV signals. The fractions containing the product were combined and driedvia centrifugal evaporation to afford4-isopropyl-2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine,TFA (10.5 mg, 0.019 mmol, 41.2% yield). LCMS retention time 1.02[QC-ACN-TFA-XB]. MS (E⁺) m/z: 435.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ11.49 (br s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 7.82 (br d, J=8.3 Hz, 1H),7.32 (br d, J=8.4 Hz, 1H), 7.17 (s, 1H), 5.06-4.89 (m, 1H), 4.36-4.17(m, 1H), 4.08 (s, 3H), 4.01 (br t, J=12.1 Hz, 1H), 3.77-3.15 (m, 6H),1.58-1.47 (m, 6H), 1.40-1.26 (m, 6H).

Example 671 2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo [1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine

Intermediate 671A: tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate

A solution of tert-butyl5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (0.925 g,2.73 mmol), 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (0.946g, 4.09 mmol), [Ir(dF(Me)ppy)₂(dtbbpy)]PF₆ (0.028 g, 0.027 mmol),2-tert-butyl-1,1,3,3-tetramethylguanidine (0.701 g, 4.09 mmol),nickel(II) chloride ethylene glycol dimethyl ether complex (0.030 g,0.136 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (0.037 g, 0.136 mmol) inDMSO (27.3 mL) in a vial with a pressure-relief septum-lined cap andstir bar was degassed with nitrogen for 15 minutes. The resultingsolution was sealed and placed in a rack with stirring and irradiationwith 34 W Kessil KSH 150B blue grow lamps and a cooling fan for 68hours. This reaction was set up in duplicate vials side by side. Uponcompletion, the duplicate reaction vials were combined and diluted withwater and DCM. The organic layer was washed with water three times,dried over sodium sulfate, filtered, and concentrated to afford a crudebrown oil. This material was purified by silica gel columnchromatography on a Teledyne Isco instrument eluting with Hex/EtOAc0-50% to afford tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(1.7 g). LCMS retention time 1.23 [TS]. MS (E⁺) m/z: 446.3 (M+H). ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.29 (br s, 1H), 7.51 (br s, 1H), 7.39 (d,J=8.5 Hz, 1H), 4.64 (dd, J=10.5, 2.7 Hz, 1H), 4.55-4.25 (m, 1H),4.16-3.88 (m, 2H), 3.76 (td, J=11.7, 2.4 Hz, 1H), 3.38-3.25 (m, 1H),3.18-3.01 (m, 1H), 3.00-2.91 (m, 1H), 1.67 (s, 9H), 1.49 (s, 9H), 1.38(d, J=6.6 Hz, 6H).

Intermediate 671B: tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate

A solution containing tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(1.67 g, 3.75 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.918 mL, 4.50mmol) in dry THF (19 mL) under a nitrogen atmosphere was cooled in a dryice/acetone bath to −78° C. and treated with LDA (2M in THF, 2.81 mL,5.62 mmol). The mixture was allowed to warm to −20° C. slowly over 2hours. The reaction mixture was then re-cooled to −60° C. and additional2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.31 mL, 1.52mmol) and LDA (2M in THF, 0.93 mL, 1.86 mmol) were added sequentially.The reaction mixture darkened, the bath was quickly changed to a −40° C.bath, and the reaction was quickly finished. Upon completion, thereaction mixture was treated with saturated aqueous NH₄Cl solution,water, and DCM. The organic layer was separated, dried over sodiumsulfate, filtered and concentrated. The crude isolate was purified viasilica gel column chromatography on a Teledyne Isco instrument elutingwith Hex/EtOAc 0-50%. Concentration of the fractions containing productprovided tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(1.65 g, 2.89 mmol, 77% yield). LCMS retention time 1.32 [TS]. MS (E⁺)m/z: 572.5 (M+H). ¹H NMR (499 MHz, CHLOROFORM-d) δ 8.01 (d, J=8.7 Hz,1H), 7.32 (d, J=8.6 Hz, 1H), 4.67-4.55 (m, 1H), 4.54-4.34 (m, 1H),4.16-3.84 (m, 2H), 3.81-3.70 (m, 1H), 3.36-3.26 (m, 1H), 3.16-2.90 (m,2H), 1.66 (s, 9H), 1.50 (s, 9H), 1.46-1.42 (m, 18H).

Intermediate 671C: tert-butyl2-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate

A vial with a pressure-relief septum-lined cap containing tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(1.65 g, 2.89 mmol) was heated with slow stirring at 165° C. undernitrogen atmosphere with an inlet of nitrogen gas from a manifold lineand then remained at room temperature overnight. Heating was thenresumed for 90 minutes until the material had formed a brown melt thatsolidified into a brown glass upon cooling to room temperature. Thematerial was dissolved in DCM, transferred to a round bottom flask, andconcentrated to obtain an off-white foam, tert-butyl2-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate,treated as quantitative recovery (2.88 mmol) and carried forward as is.Note: observed conversion to boronic acid when analyzed on LCMS,although NMR indicated that the product was purely the compound. LCMSretention time 0.73 (boronic acid) [TS]. MS (E⁺) m/z: 390.2 (boronicacid). ¹H NMR (499 MHz, CHLOROFORM-d) δ 8.27 (br s, 1H), 7.58 (d, J=8.5Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.65-4.61 (m, 1H), 4.59-4.32 (m, 1H),4.13-3.86 (m, 2H), 3.82-3.67 (m, 2H), 3.04 (br dd, J=13.4, 10.7 Hz, 2H),1.52-1.48 (m, 15H), 1.36 (s, 12H).

Intermediate 671D: tert-butyl2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate

To a solution of tert-butyl2-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(197 mg, 0.418 mmol), 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(105 mg, 0.460 mmol), and 2^(nd) generation Xphos precatalyst (16.4 mg,0.021 mmol) in 1,4-dioxane (2.8 mL) was added aqueous K₃PO₄ (2M, 627 μl,1.254 mmol), and the biphasic mixture was degassed with nitrogen for 5min. The reaction vessel was sealed and stirred at 70° C. for 2 hours.Upon completion, the reaction mixture was cooled to room temperature andconcentrated. The crude material was suspended in DCM and purified bysilica gel column chromatography on a Teledyne Isco instrument elutingwith Hex/EtOAc 0-100% to give tert-butyl2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(177 mg, 0.359 mmol, 86% yield). LCMS retention time 0.82 [TS]. MS (ES⁺)m/z: 493.6 (M+H).

Example 671

To a solution of tert-butyl2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(8.9 mg, 0.018 mmol) in DCM (0.5 mL) at room temperature was added TFA(0.5 mL). The reaction mixture was concentrated after 30 minutes to givecrude material which was taken up in DMF with a few drops of Et₃N andpurified via preparative LC/MS with the following conditions: Column:Xbridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 3-40% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Thefractions containing the product were combined and dried via centrifugalevaporation to afford2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine(5.3 mg, 0.013 mmol, 72.4% yield). LCMS retention time 0.97[QC-ACN-AA-XB]. MS (E⁺) m/z: 393.1. NMR (500 MHz, DMSO-d₆) δ 11.43 (s,1H), 8.62 (s, 1H), 8.51 (s, 1H), 7.73 (br d, J=8.5 Hz, 1H), 7.22 (br d,J=8.2 Hz, 1H), 7.18 (s, 1H), 4.57 (br d, J=8.5 Hz, 1H), 4.07 (s, 3H),3.93 (br d, J=10.4 Hz, 1H), 3.74-3.62 (m, 1H), 3.56-3.44 (m, 1H),3.36-3.23 (m, 1H), 3.23-3.16 (m, 1H), 2.81 (br s, 2H), 2.71 (br t,J=11.3 Hz, 1H), 1.52 (br d, J=6.7 Hz, 6H). For the derivatization ofthis material, this procedure was repeated on larger scale as describedhere: To a solution of tert-butyl2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine-4-carboxylate(112 mg, 0.227 mmol) in DCM (6 mL) at room temperature was added TFA (3mL). The reaction mixture was concentrated after 30 minutes to givematerial considered quantitative recovery of2-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)morpholine,TFA (0.227 mmol). Carried forward as is.

Example 6806-(3-isopropyl-5-(piperazin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

A mixture of tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(72.3 mg, 0.100 mmol),1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (49.6 mg, 0.150mmol), [Ir(dF(Me)ppy)₂(dtbbpy)]PF₆ (1.0 mg, 1.000 μmol),2-tert-butyl-1,1,3,3-tetramethylguanidine (25.7 mg, 0.150 mmol),nickel(II) chloride ethylene glycol dimethyl ether complex (1.1 mg, 5.00μmol), and 4,4′-di-tert-butyl-2,2′-bipyridine (1.3 mg, 5.00 μmop in DMSO(3 mL) in a vial with a pressure-relief septum-lined cap and stir barwas degassed with nitrogen for 15 minutes. The resulting mixture wassealed and placed in a rack with stirring and irradiation with 34 WKessil KSH 150B blue grow lamps and a cooling fan for 48 hours. Uponcompletion, the reaction mixture was diluted with water and DCM. Theorganic layer was washed with water three times, dried over sodiumsulfate, filtered, and concentrated to afford a crude brown oil. Thecrude material was partially purified by silica gel columnchromatography on a Teledyne Isco instrument eluting with Hex/EtOAc0-50% to give material that still contained a significant amount ofimpurities. This material was carried forward and suspended in DCM (1mL) and TFA (1 mL) and stirred for 30 minutes at room temperature. Uponcompletion, the material was concentrated and suspended in TFA (2 mL)with stirring for 3 hours at room temperature. Upon completion, thereaction mixture was concentrated, dissolved in methanol with a fewdrops of Et₃N, and purified via the following conditions: Column:Xbridge C18, 200 mm×30 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 2-minute hold at 100% B;Flow Rate: 45 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the product werecombined and dried via centrifugal evaporation to afford6-(3-isopropyl-5-(piperazin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (9.5 mg, 0.019 mmol, 19% yield). LCMS retention time 0.91[QC-ACN-TFA-XB]. MS (E+) m/z: 390.0 (M+H). Select NMR peaks: ¹H NMR (500MHz, DMSO-d₆) δ 11.60 (s, 1H), 8.82 (s, 1H), 8.48 (s, 1H), 7.86 (d,J=8.5 Hz, 1H), 7.30 (br d, J=8.5 Hz, 1H), 4.83 (br d, J=10.4 Hz, 1H),3.92 (br d, J=13.4 Hz, 1H), 2.97 (dt, J=13.5, 6.5 Hz, 1H), 2.59 (s, 3H),2.13 (s, 3H), 1.40 (br d, J=4.9 Hz, 6H)

The following examples were prepared according to the general proceduresdescribed in the above examples.

TABLE 1 Ret Ex. Mol. LCMS Time HPLC No. Structure Wt. M⁺ (min) Method 12

403.53 404.3 1.2 QC- ACN- AA-XB  13

405.51 406.3 0.71 QC- ACN- TFA- XB 314

375.48 376.3 0.96 QC- ACN- AA-XB  15

460.59 461.5 0.76 QC- ACN- TFA- XB  16

377.45 378.2 0.67 QC- ACN- TFA- XB  17

462.56 463.4 1.06 QC- ACN- AA-XB  18

462.56 463.2 0.7 QC- ACN- TFA- XB  19

474.61 475.1 1 QC- ACN- TFA- XB  20

389.51 390.2 1.14 QC- ACN- AA-XB  21

474.61 475.2 0.76 QC- ACN- TFA- XB  22

460.59 460.9 0.97 QC- ACN- TFA- XB  23

389.51 390.1 1.05 QC- ACN- TFA- XB  24

473.63 474.2 1.52 QC- ACN- AA-XB  25

474.61 475.1 1.18 QC- ACN- TFA- XB  26

460.59 460.9 0.68 QC- ACN- TFA- XB  27

462.56 463.4 0.81 QC- ACN- AA-XB  28

476.59 477.4 1.04 QC- ACN- AA-XB  29

461.57 462.1 0.73 QC- ACN- TFA- XB  30

461.57 462.3 1.41 QC- ACN- AA-XB  31

391.48 392.2 0.67 QC- ACN- TFA- XB  32

360.47 361.2 1.19 QC- ACN- AA-XB  33

444.58 445.1 1.37 QC- ACN- AA-XB  34

445.57 446.1 0.82 QC- ACN- TFA- XB  35

360.47 361.1 0.82 QC- ACN- AA-XB  36

444.58 445.2 1.12 QC- ACN- AA-XB  37

445.57 446.1 0.72 QC- ACN- TFA- XB  38

376.46 377.2 0.88 QC- ACN- TFA- XB  39

445.57 446.1 0.77 QC- ACN- TFA- XB  40

459.60 460.1 1.25 QC- ACN- AA-XB  41

493.63 494 1.46 QC- ACN- AA-XB  42

502.62 503.1 1.66 QC- ACN- AA-XB  43

429.57 430.4 1.1 QC- ACN- AA-XB  44

514.68 515.4 1.29 QC- ACN- AA-XB  45

535.71 536.4 0.84 QC- ACN- TFA- XB  46

471.65 472.1 1.42 QC- ACN- AA-XB  47

485.64 486.4 0.8 QC- ACN- TFA- XB  48

565.69 566.6 0.81 QC- ACN- TFA- XB  49

487.65 488.3 1.46 QC- ACN- AA-XB  50

403.53 404.3 0.74 QC- ACN- TFA- XB  51

466.59 467.2 1.27 QC- ACN- AA-XB  52

466.59 467.2 1.36 QC- ACN- AA-XB  53

494.66 495.2 1.56 QC- ACN- AA-XB  54

558.73 559.2 1.64 QC- ACN- AA-XB  55

501.68 502.2 0.8 QC- ACN- TFA- XB  56

501.66 502.2 1.62 QC- ACN- AA-XB  57

457.63 458.2 0.85 QC- ACN- TFA- XB  58

471.65 472.3 0.89 QC- ACN- TFA- XB  59

471.65 471.9 1.58 QC- ACN- AA-XB  60

509.66 510.2 1.49 QC- ACN- AA-XB  61

569.71 570.2 1.64 QC- ACN- AA-XB  62

511.68 512.2 0.85 QC- ACN- TFA- XB  63

512.67 513 0.82 QC- ACN- TFA- XB  64

523.69 524.2 1.72 QC- ACN- AA-XB  65

473.63 474.2 0.79 QC- ACN- TFA- XB  66

445.62 446.1 1.22 QC- ACN- AA-XB  67

539.69 540.3 0.84 QC- ACN- TFA- XB  68

512.67 513.2 1.28 QC- ACN- AA-XB  69

555.69 556.1 1.14 QC- ACN- TFA- XB  70

459.64 460.3 1.39 QC- ACN- AA-XB  71

707.84 708.5 1.13 QC- ACN- TFA- XB  72

525.66 526.3 1.64 QC- ACN- AA-XB  73

593.74 594.1 1.56 QC- ACN- AA-XB  74

615.79 616.2 1.18 QC- ACN- TFA- XB  75

647.79 648.5 1.07 QC- ACN- TFA- XB  76

593.74 594.2 1.54 QC- ACN- AA-XB  77

515.68 516.8 1.67 QC- ACN- AA-XB  78

509.66 510.3 1.15 QC- ACN- AA-XB  79

405.51 406.1 0.65 QC- ACN- TFA- XB  80

489.62 490.4 0.73 QC- ACN- TFA- XB  81

461.57 462.3 0.62 QC- ACN- TFA- XB  82

489.62 489.9 1.32 QC- ACN- AA-XB  83

444.54 445.4 1.33 QC- ACN- AA-XB  84

490.61 491 1.24 QC- ACN- TFA- XB  85

490.61 490.9 0.9 QC- ACN- TFA- XB  86

459.60 460 0.83 QC- ACN- TFA- XB  87

535.71 536.2 0.89 QC- ACN- TFA- XB  88

375.48 376.3 1.09 QC- ACN- AA-XB  89

391.48 392.3 0.98 QC- ACN- AA-XB  90

476.59 477.22 1.44 QC- ACN- AA-XB  91

405.51 406.2 1.48 QC- ACN- AA-XB  92

433.56 434.4 1.01 QC- ACN- TFA- XB  93

447.54 448.4 0.93 QC- ACN- TFA- XB  94

430.52 431.3 1.58 QC- ACN- AA-XB  95

497.62 498.2 1.6 QC- ACN- AA-XB  96

403.53 404.3 1.31 QC- ACN- AA-XB  97

473.63 474.4 1.84 QC- ACN- AA-XB  98

488.64 489.4 1.23 QC- ACN- AA-XB  99

490.61 491.2 1.12 QC- ACN- AA-XB 100

431.59 432.11 1.62 QC- ACN- AA-XB 101

473.63 474.4 1.5 QC- ACN- AA-XB 102

475.60 476.4 0.84 QC- ACN- TFA- XB 103

461.57 462.2 1.47 QC- ACN- AA-XB 104

475.60 476.4 0.84 QC- ACN- TFA- XB 105

461.61 461.9 1.92 QC- ACN- AA-XB 106

463.59 464 1.5 QC- ACN- AA-XB 107

475.60 476.2 1.72 QC- ACN- AA-XB 108

445.57 446.2 1.13 QC- ACN- TFA- XB 109

447.59 447.9 2.18 QC- ACN- AA-XB 110

461.61 462.2 2.07 QC- ACN- AA-XB 111

461.61 462.2 1.3 QC- ACN- TFA- XB 112

463.59 464.2 1.7 QC- ACN- AA-XB 113

489.62 490.2 1.04 QC- ACN- TFA- XB 114

475.64 475.9 1.42 QC- ACN- TFA- XB 115

447.59 448.3 1.89 QC- ACN- AA-XB 116

487.53 488.3 2.06 QC- ACN- AA-XB 117

449.56 450.3 1.47 QC- ACN- AA-XB 118

463.59 463.9 1.42 QC- ACN- AA-XB 119

419.53 420.13 1.04 QC- ACN- TFA- XB 120

445.57 446.2 0.97 QC- ACN- TFA- XB 121

516.65 517.1 1.54 QC- ACN- AA-XB 122

375.48 376.11 1.17 QC- ACN- AA-XB 123

460.59 461.2 0.88 QC- ACN- TFA- XB 124

474.61 475.4 0.67 QC- ACN- TFA- XB 125

389.51 390.3 1.25 QC- ACN- AA-XB 126

417.56 418.3 0.75 QC- ACN- TFA- XB 127

459.60 460.4 1.43 QC- ACN- AA-XB 128

476.59 477.4 1.41 QC- ACN- AA-XB 129

486.58 487.4 0.87 QC- ACN- TFA- XB 130

448.53 449.4 1.29 QC- ACN- AA-XB 131

449.56 450.37 0.93 QC- ACN- TFA- XB 132

511.65 512.2 1.51 QC- ACN- AA-XB 133

523.66 524.3 1.65 QC- ACN- AA-XB 134

512.63 513.3 1.47 QC- ACN- AA-XB 135

501.56 502.4 1.14 QC- ACN- TFA- XB 136

490.61 491.2 1.08 QC- ACN- TFA- XB 137

462.56 463 1.28 QC- ACN- AA-XB 138

462.56 463.4 1.4 QC- ACN- AA-XB 139

403.49 404.2 0.87 QC- ACN- TFA- XB 140

459.55 460.3 1.05 QC- ACN- TFA- XB 141

488.60 489.4 1.28 QC- ACN- AA-XB 142

417.52 418.3 1.34 QC- ACN- AA-XB 143

516.65 517.4 1.49 QC- ACN- AA-XB 144

474.61 475.1 1.11 QC- ACN- TFA- XB 145

500.65 501.2 1.47 QC- ACN- TFA- XB 146

486.62 487.4 0.8 QC- ACN- TFA- XB 147

509.67 510.4 1.41 QC- ACN- AA-XB 148

442.57 443.2 1.82 QC- ACN- AA-XB 149

460.59 460.9 1.41 QC- ACN- AA-XB 150

403.49 404.4 1.36 QC- ACN- AA-XB 151

524.69 525.1 1.74 QC- ACN- AA-XB 152

403.53 404.1 1.95 QC- ACN- AA-XB 153

403.53 404.1 1.31 QC- ACN- AA-XB 154

516.65 517.2 1.14 QC- ACN- TFA- XB 155

516.65 517.2 1.49 QC- ACN- AA-XB 156

500.65 501.2 1.4 QC- ACN- AA-XB 157

488.64 488.9 1.38 QC- ACN- AA-XB 158

490.61 491.1 1.05 QC- ACN- TFA- XB 159

504.64 1009.4 (2M + H) 1.4 QC- ACN- AA-XB 160

530.68 531.2 1.35 QC- ACN- AA-XB 161

500.65 501.20 1.43 QC- ACN- TFA- XB 162

403.53 404.3 0.8 QC- ACN- TFA- XB 163

488.64 489.3 1.38 QC- ACN- AA-XB 164

445.57 446.4 1.43 QC- ACN- AA-XB 165

521.68 522.4 0.83 QC- ACN- TFA- XB 166

471.61 471.9 1.06 QC- ACN- TFA- XB 167

446.60 447.2 1.06 QC- ACN- TFA- XB 168

460.63 461.2 1.35 QC- ACN- AA-XB 169

462.60 463 1.21 QC- ACN- AA-XB 170

460.63 461 1.56 QC- ACN- AA-XB 171

458.61 459.4 0.77 QC- ACN- TFA- XB 172

458.61 459.3 1.49 QC- ACN- AA-XB 173

488.64 489 1.28 QC- ACN- AA-XB 174

458.61 459.2 1.02 QC- ACN- TFA- XB 175

471.61 472.2 0.75 QC- ACN- TFA- XB 176

403.49 404.2 1.68 QC- ACN- AA-XB 177

432.57 433.1 1.29 QC- ACN- AA-XB 178

460.58 461.4 0.73 QC- ACN- TFA- XB 179

432.57 433.1 1 QC- ACN- TFA- XB 180

460.58 461.1 1.6 QC- ACN- AA-XB 181

489.62 490.3 1.14 QC- ACN- AA-XB 182

472.64 473.4 0.92 QC- ACN- TFA- XB 183

472.64 473.3 1.42 QC- ACN- AA-XB 184

443.60 444.2 1.51 QC- ACN- AA-XB 185

443.60 444.3 0.88 QC- ACN- TFA- XB 186

460.58 461.5 0.75 QC- ACN- TFA- XB 187

432.57 433.3 1.26 QC- ACN- AA-XB 188

418.55 419.2 0.67 QC- ACN- TFA- XB 189

418.55 419.1 1.28 QC- ACN- AA-XB 190

510.65 511.2 1.23 QC- ACN- AA-XB 191

462.60 463 1.07 QC- ACN- AA-XB 192

458.61 459.1 1.31 QC- ACN- AA-XB 193

446.60 447.1 1.48 QC- ACN- AA-XB 194

474.61 475.2 0.98 QC- ACN- TFA- XB 195

458.61 459.3 0.76 QC- ACN- TFA- XB 196

510.65 511.5 1.43 QC- ACN- AA-XB 197

488.64 489 1.16 QC- ACN- AA-XB 198

476.63 477.3 1.19 QC- ACN- AA-XB 199

458.61 459.2 0.79 QC- ACN- TFA- XB 200

486.66 487.4 1.58 QC- ACN- AA-XB 201

486.66 487.1 1.53 QC- ACN- AA-XB 202

524.67 525.2 0.81 QC- ACN- TFA- XB 203

524.67 525.4 0.81 QC- ACN- TFA- XB 204

485.59 486.3 1.26 QC- ACN- AA-XB 205

493.66 494.2 1.17 QC- ACN- TFA- XB 206

485.59 486.2 1.7 QC- ACN- AA-XB 207

493.66 494.2 0.94 QC- ACN- TFA- XB 208

510.65 511.4 0.87 QC- ACN- TFA- XB 209

510.65 511.32 1.19 QC- ACN- AA-XB 210

489.62 490.4 1.06 QC- ACN- TFA- XB 211

503.65 504.4 1.11 QC- ACN- AA-XB 212

475.60 476.1 1.17 QC- ACN- AA-XB 213

503.65 504.3 1.16 QC- ACN- AA-XB 214

474.61 475.3 0.85 QC- ACN- TFA- XB 215

460.58 461.1 1.21 QC- ACN- AA-XB 216

489.62 490.3 0.78 QC- ACN- TFA- XB 217

510.65 511.4 0.83 QC- ACN- TFA- XB 218

485.60 486.1 1.06 QC- ACN- AA-XB 219

536.70 537.3 1.62 QC- ACN- AA-XB 220

460.58 461.3 0.76 QC- ACN- TFA- XB 221

485.60 486.1 0.63 QC- ACN- TFA- XB 222

489.62 490.3 1.07 QC- ACN- AA-XB 223

536.70 537.3 0.85 QC- ACN- TFA- XB 224

510.65 511.3 1.03 QC- ACN- AA-XB 225

475.60 476.4 1.37 QC- ACN- AA-XB 226

503.65 504.4 1.32 QC- ACN- AA-XB 227

489.62 490.1 0.73 QC- ACN- TFA- XB 228

489.62 490.3 1.53 QC- ACN- AA-XB 229

474.61 475.1 0.76 QC- ACN- TFA- XB 230

503.65 504.3 1.24 QC- ACN- AA-XB 231

489.62 490.3 1.1 QC- ACN- AA-XB 232

489.62 490.3 1.26 QC- ACN- AA-XB 233

458.61 459.4 1.27 QC- ACN- AA-XB 234

458.61 459.3 1.09 QC- ACN- AA-XB 235

460.58 461.3 0.62 QC- ACN- TFA- XB 236

519.71 520 1.8 QC- ACN- AA-XB 237

498.68 499.2 1.79 QC- ACN- AA-XB 238

519.71 520.3 0.93 QC- ACN- TFA- XB 239

498.68 499.3 1.9 QC- ACN- AA-XB 240

474.61 475.2 1.53 QC- ACN- AA-XB 241

524.68 525.2 0.76 QC- ACN- TFA- XB 242

524.68 525.3 1.58 QC- ACN- AA-XB 243

427.60 428.1 1.52 QC- ACN- AA-XB 244

486.62 487.3 1.1 QC- ACN- AA-XB 245

469.63 470.3 1.35 QC- ACN- AA-XB 246

474.61 475.3 0.63 QC- ACN- TFA- XB 247

493.67 494.3 0.92 QC- ACN- TFA- XB 248

534.68 535.2 1.52 QC- ACN- AA-XB 249

462.64 463.1 0.75 QC- ACN- TFA- XB 250

448.61 449 1.55 QC- ACN- AA-XB 251

493.67 494.3 1.47 QC- ACN- AA-XB 252

474.61 475.3 1.34 QC- ACN- AA-XB 253

534.68 535.2 1.32 QC- ACN- AA-XB 254

462.64 463.3 1.55 QC- ACN- AA-XB 255

517.69 518.1 1.45 QC- ACN- AA-XB 256

517.69 518.2 1 QC- ACN- TFA- XB 257

564.75 565.3 1.3 QC- ACN- AA-XB 258

561.75 562.4 1.23 QC- ACN- AA-XB 259

611.82 612.2 1.52 QC- ACN- AA-XB 260

480.63 481.3 1.49 QC- ACN- AA-XB 261

564.75 565.5 0.9 QC- ACN- AA-XB 262

611.82 612.4 1.74 QC- ACN- AA-XB 263

426.57 427.3 1.28 QC- ACN- AA-XB 264

493.67 494.1 0.88 QC- ACN- TFA- XB 265

471.65 472.4 1.37 QC- ACN- AA-XB 266

563.76 564.2 0.92 QC- ACN- TFA- XB 267

471.65 472.4 1.48 QC- ACN- AA-XB 268

496.66 497.4 1.47 QC- ACN- AA-XB 269

493.67 494.4 1.27 QC- ACN- AA-XB 270

426.57 427.3 1.38 QC- ACN- AA-XB 271

563.76 564.1 1.44 QC- ACN- AA-XB 272

497.65 498.4 0.98 QC- ACN- TFA- XB 273

518.68 519.1 1.57 QC- ACN- AA-XB 274

496.66 497.2 1.44 QC- ACN- AA-XB 275

518.68 519.3 1.47 QC- ACN- AA-XB 276

497.65 498.4 1.41 QC- ACN- AA-XB 277

499.62 500 1.27 QC- ACN- TFA- XB 278

521.72 522.3 0.99 QC- ACN- TFA- XB 279

444.58 445.3 1.31 QC- ACN- AA-XB 280

473.63 474.4 0.81 QC- ACN- TFA- XB 281

470.62 471.2 0.77 QC- ACN- TFA- XB 282

418.59 419 1.55 QC- ACN- AA-XB 283

444.62 445 1.45 QC- ACN- AA-XB 284

444.58 445.3 0.79 QC- ACN- TFA- XB 285

521.72 522.4 1.96 QC- ACN- AA-XB 286

444.62 445.19 1.57 QC- ACN- TFA- XB 287

418.59 419.3 0.62 QC- ACN- TFA- XB 288

470.62 471.2 0.79 QC- ACN- TFA- XB 289

485.68 486.3 1.07 QC- ACN- TFA- XB 290

483.66 484.4 1.05 QC- ACN- TFA- XB 291

486.66 487.4 1.06 QC- ACN- TFA- XB 292

485.68 486.4 1.58 QC- ACN- AA-XB 293

402.54 403.2 1.62 QC- ACN- AA-XB 294

483.66 484.3 1.52 QC- ACN- AA-XB 295

431.58 432.2 1.12 QC- ACN- TFA- XB 296

402.55 403.3 1.06 QC- ACN- AA-XB 297

402.55 403.32 QC- ACN- AA-XB 299

431.58 432.4 0.78 QC- ACN- TFA- XB 300

402.55 403.1 1.49 QC- ACN- TFA- XB 301

402.55 403.3 1.14 QC- ACN- AA-XB 302

401.56 402.1 0.8 QC- ACN- TFA- XB 303

473.63 474.2 1.14 QC- ACN- AA-XB 304

494.66 495.2 0.64 QC- ACN- TFA- XB 305

472.64 473.3 1.22 QC- ACN- AA-XB 306

526.66 527.1 1.68 QC- ACN- AA-XB 307

500.57 501.4 1.53 QC- ACN- AA-XB 308

500.57 501.1 1.01 QC- ACN- TFA- XB 309

474.61 475.3 1.6 E 310

488.64 489 1.66 E 311

488.64 489.4 1.81 E 312

502.66 503.3 1.5 E 313

460.63 461.3 1.44 E 314

490.65 491.4 1.46 E 315

502.66 503 1.67 E 316

474.61 475.4 1.69 E 317

500.65 501.3 1.51 E 318

418.55 419.3 1.24 E 319

500.65 501.3 1.5 E 320

460.63 461.4 1.44 E 321

490.65 491.4 1.4 E 322

482.58 483.3 2.01 E 323

418.55 419.3 1.26 E 324

482.58 483 2.16 E 325

458.61 459 1.39 E 326

458.61 459 1.15 E 327

476.63 477.4 1.46 E 328

488.64 489 1.45 E 329

488.64 489 1.52 E 330

488.64 489 1.8 E 331

488.64 489.3 1.83 E 332

527.68 528.4 1.51 E 333

527.68 528.4 1.49 E 334

502.71 503 1.8 E 335

476.63 477 1.43 E 336

502.71 503 1.89 E 337

494.59 495.3 2.1 E 338

494.59 495.3 2.35 E 339

485.64 486.3 1.95 E 340

485.64 486.4 2 E 341

506.63 507 1.57 E 342

506.63 507 1.76 E 343

504.61 505.3 1.65 E 344

504.61 505.3 1.71 E 345

478.57 479.3 1.65 E 346

478.57 479.3 1.77 E 347

436.54 437 1.33 E 348

436.54 437 1.41 E 349

401.51 402.3 1.69 QC- ACN- AA-XB 350

458.61 459.5 1.32 QC- ACN- AA-XB 351

458.61 459 1.67 QC- ACN- AA-XB 352

487.65 488.5 0.8 QC- ACN- TFA- XB 353

430.60 431.5 1.19 QC- ACN- AA-XB 354

487.65 488.4 0.8 QC- ACN- TFA- XB 355

430.60 431.3 0.8 QC- ACN- TFA- XB 356

430.60 431.1 1.31 QC- ACN- AA-XB 357

508.67 509 1.26 QC- ACN- AA-XB 358

444.63 445.4 0.81 QC- ACN- TFA- XB 359

508.67 509 1.42 QC- ACN- AA-XB 360

456.64 457.1 0.85 QC- ACN- TFA- XB 361

469.64 470.2 0.74 QC- ACN- TFA- XB 362

472.64 473.2 1.28 QC- ACN- AA-XB 363

444.63 445.4 1.37 QC- ACN- AA-XB 364

458.65 459.1 1.43 QC- ACN- AA-XB 365

460.63 461.2 1.25 QC- ACN- AA-XB 366

469.64 470 1.69 QC- ACN- AA-XB 367

416.57 418.3 1.2 QC- ACN- AA-XB 368

501.68 502.3 1.23 QC- ACN- AA-XB 369

416.57 417.1 1.32 QC- ACN- AA-XB 370

478.59 478.9 2.06 QC- ACN- AA-XB 371

440.60 440.9 1.7 QC- ACN- AA-XB 372

486.66 486.9 1.08 QC- ACN- TFA- XB 373

498.60 498.9 1.87 QC- ACN- AA-XB 374

478.59 479.2 1.12 QC- ACN- TFA- XB 375

440.60 441.2 1.06 QC- ACN- TFA- XB 376

498.60 499.2 1.68 QC- ACN- AA-XB 377

486.66 486.9 1.32 QC- ACN- AA-XB 378

458.65 458.97 1.1 QC- ACN- TFA-XB 379

446.60 446.9 0.95 QC- ACN- TFA- XB 380

456.64 457.1 1.41 QC- ACN- AA-XB 381

506.65 506.9 1.14 QC- ACN- TFA- XB 382

520.70 521.2 1.08 QC- ACN- TFA- XB 383

520.70 521.1 1.82 QC- ACN- AA-XB 384

455.61 456.2 1.45 QC- ACN- AA-XB 385

506.65 506.9 1.13 QC- ACN- TFA- XB 386

442.61 443.19 1.01 QC- ACN- AA-XB 387

456.64 457.2 0.78 QC- ACN- TFA- XB 388

444.63 445.3 0.78 QC- ACN- TFA- XB 389

474.65 475.1 1.27 QC- ACN- AA-XB 390

444.63 445.3 1.3 QC- ACN- AA-XB 391

474.65 475.3 1.36 QC- ACN- AA-XB 392

486.66 487.4 0.79 QC- ACN- TFA- XB 393

486.66 487 1.17 QC- ACN- AA-XB 394

522.70 523.1 1.56 QC- ACN- AA-XB 395

538.70 539.3 1.85 QC- ACN- AA-XB 396

501.68 502.3 1.27 QC- ACN- AA-XB 397

497.65 498.2 1.3 QC- ACN- AA-XB 398

473.63 474.3 1.56 QC- ACN- AA-XB 399

497.65 520.1 1.4 QC- ACN- AA-XB 400

487.65 488.2 0.79 QC- ACN- TFA- XB 401

472.64 473.2 1.54 QC- ACN- AA-XB 402

522.70 523.2 1.8 QC- ACN- AA-XB 403

487.65 488.1 1.66 QC- ACN- AA-XB 404

501.68 502.2 1.49 QC- ACN- AA-XB 405

538.70 539.2 0.86 QC- ACN- TFA- XB 406

473.63 474.1 1.53 QC- ACN- AA-XB 407

456.64 457.2 1.43 QC- ACN- AA-XB 408

501.68 502.2 1.44 QC- ACN- AA-XB 409

446.60 447 0.99 QC- ACN- TFA- XB 410

501.68 502.2 0.84 QC- ACN- TFA- XB 411

458.65 459.4 1.39 QC- ACN- AA-XB 412

483.62 484.1 1.19 QC- ACN- AA-XB 413

483.62 484.4 1.48 QC- ACN- AA-XB 414

522.70 523.2 0.83 QC- ACN- TFA- XB 415

522.70 523.4 1.37 QC- ACN- AA-XB 416

483.62 484.1 1.57 QC- ACN- AA-XB 417

508.67 509.2 1.41 QC- ACN- AA-XB 418

508.67 509.3 1.55 QC- ACN- AA-XB 419

534.72 535.3 1.66 QC- ACN- AA-XB 420

487.65 488.3 1.37 QC- ACN- AA-XB 421

442.61 443.1 1.29 QC- ACN- AA-XB 422

487.65 488.29 1.48 QC- ACN- AA-XB 423

562.66 563.4 1.39 QC- ACN- TFA- XB 424

472.64 473.3 1.38 QC- ACN- AA-XB 425

522.71 523.2 1.44 QC- ACN- AA-XB 426

442.61 443.3 1.31 QC- ACN- AA-XB 427

522.71 523.2 1.62 QC- ACN- AA-XB 428

495.68 496.2 2.22 QC- ACN- AA-XB 429

460.63 461 1.21 QC- ACN- AA-XB 430

472.64 473.4 0.77 QC- ACN- TFA- XB 431

460.63 461 0.83 QC- ACN- TFA- XB 432

455.61 456.2 1.23 QC- ACN- TFA- XB 433

495.68 496.1 2.34 QC- ACN- AA-XB 434

467.62 467.9 0.79 QC- ACN- TFA- XB 435

484.65 485.2 0.81 QC- ACN- TFA- XB 436

467.62 468.3 1.96 QC- ACN- AA-XB 437

484.65 485.3 1.14 QC- ACN- AA-XB 438

532.71 533.4 1.41 QC- ACN- AA-XB 439

458.61 459.4 1.01 QC- ACN- TFA- XB 440

458.61 459.3 0.97 QC- ACN- TFA- XB 441

497.65 497.9 1.77 QC- ACN- AA-XB 442

499.66 500.2 1.51 QC- ACN- AA-XB 443

499.66 500.2 1.58 QC- ACN- AA-XB 444

502.66 503.1 1.45 QC- ACN- AA-XB 445

520.70 521.4 0.81 QC- ACN- TFA- XB 446

509.67 510.3 0.78 QC- ACN- TFA- XB 447

509.67 510.4 0.8 QC- ACN- TFA- XB 448

520.70 521.4 0.83 QC- ACN- TFA- XB 449

529.69 530.3 1.4 QC- ACN- AA-XB 450

508.69 509.4 1.25 QC- ACN- AA-XB 451

486.66 487.3 0.9 QC- ACN- TFA- XB 452

508.69 509.4 0.84 QC- ACN- TFA- XB 453

486.66 487.4 1.41 QC- ACN- AA-XB 454

536.74 537.2 0.84 QC- ACN- TFA- XB 455

536.74 537.4 1.86 QC- ACN- AA-XB 456

526.69 527.4 1.09 QC- ACN- TFA- XB 457

547.72 548.4 1.86 QC- ACN- AA-XB 458

547.72 548.1 1.78 QC- ACN- AA-XB 459

526.69 527.4 1.8 QC- ACN- AA-XB 460

536.74 537.2 0.77 QC- ACN- TFA- XB 461

552.74 553.4 0.86 QC- ACN- TFA- XB 462

515.71 516.1 0.94 QC- ACN- TFA- XB 463

531.71 532.4 0.95 QC- ACN- TFA- XB 464

548.75 549.1 0.85 QC- ACN- TFA- XB 465

520.70 521.4 1.46 QC- ACN- AA-XB 466

402.55 403.3 0.85 QC- ACN- TFA- XB 467

515.71 516.4 0.78 QC- ACN- TFA- XB 468

531.71 532.4 1.52 QC- ACN- AA-XB 469

402.55 403.3 0.87 QC- ACN- TFA- XB 470

520.70 521.4 1.84 QC- ACN- AA-XB 471

548.75 549.4 0.96 QC- ACN- TFA- XB 472

472.64 473.4 0.8 QC- ACN- TFA- XB 473

472.64 473.4 0.82 QC- ACN- TFA- XB 474

486.66 487.1 1.18 QC- ACN- AA-XB 475

573.76 574.5 1.86 QC- ACN- AA-XB 476

548.75 549.4 2.17 QC- ACN- AA-XB 477

486.66 487.5 1.34 QC- ACN- AA-XB 478

573.76 574.2 1.62 QC- ACN- TFA- XB 479

548.75 549.5 1.95 QC- ACN- AA-XB 480

562.78 563.5 0.93 QC- ACN- TFA- XB 481

578.78 579.3 1.85 QC- ACN- AA-XB 482

578.78 579.5 1.85 QC- ACN- AA-XB 483

488.64 489.4 0.76 QC- ACN- TFA- XB 484

488.64 489.2 1.04 QC- ACN- TFA- XB 485

515.71 516.5 1.59 QC- ACN- AA-XB 486

531.71 267 1.13 QC- ACN- TFA- XB 487

501.68 502.4 0.81 QC- ACN- TFA- XB 488

531.71 532.6 1.52 QC- ACN- AA-XB 489

515.71 516.5 1.9 QC- ACN- AA-XB 490

529.69 552.2 1.38 QC- ACN- AA-XB 491

428.58 429.4 1.26 QC- ACN- AA-XB 492

470.67 236.1 1.51 QC- ACN- AA-XB 493

470.67 471.4 2.55 QC- ACN- TFA- XB 494

541.74 542.3 2.34 QC- ACN- AA-XB 495

515.71 516.5 0.88 QC- ACN- TFA- XB 496

557.74 558.3 1.03 QC- ACN- TFA- XB 497

541.74 564.2 2.33 QC- ACN- AA-XB 498

557.74 558.4 0.92 QC- ACN- TFA- XB 499

546.72 547.4 1.56 QC- ACN- AA-XB 500

546.72 547 1.09 QC- ACN- TFA- XB 501

473.63 474.5 0.87 QC- ACN- TFA- XB 502

472.64 473.4 1.69 E 503

472.64 473.3 1.74 E 504

504.65 505.3 1.48 E 505

504.65 505.4 1.54 E 506

420.54 421.3 1.31 E 507

420.54 421.3 1.36 E 508

533.70 534 1.59 E 509

533.70 534.3 1.66 E 510

554.73 555.4 2.09 E 511

554.73 555.3 2.03 E 512

348.49 349.3 1.63 QC- ACN- AA-XB 513

350.47 351.3 0.58 QC- ACN- TFA- XB 514

365.48 366 0.67 QC- ACN- TFA- XB 515

364.49 365.3 0.99 QC- ACN- AA-XB 516

374.49 375.1 1.15 QC- ACN- AA-XB 517

375.48 376 0.99 QC- ACN- TFA- XB 518

374.49 374.9 0.95 QC- ACN- AA-XB 519

378.52 379 1.47 QC- ACN- AA-XB 520

390.49 391.4 0.52 B1 521

388.52 389.3 0.58 B1 522

362.52 363.3 1.46 E 523

404.52 405.1 1.25 E 524

408.48 409.1 1.23 E 525

388.52 389.2 2.46 R 526

379.50 380.7 2.524 D 527

448.61 449.3 0.52 B1 528

420.56 421.3 0.51 B1 529

449.60 450.3 0.52 B1 530

435.57 436.3 0.51 B1 531

449.60 450.3 0.51 B1 532

445.57 446.3 0.54 B1 533

459.60 460.3 0.55 B1 534

430.56 431.3 0.55 B1 535

446.56 447 0.53 B1 536

461.57 462 1.4 QC- ACN- AA-XB 537

475.60 476.1 0.72 QC- ACN- TFA- XB 538

444.58 445.3 0.55 B1 539

459.60 460.3 0.55 B1 540

473.63 474.4 0.56 B1 541

460.63 461.4 0.58 B1 542

434.58 435.4 0.53 B1 543

462.64 463.4 0.55 B1 544

449.60 450.4 0.52 B1 545

463.63 464.4 0.54 B1 546

450.63 451.4 0.55 B1 547

446.60 447.3 0.55 B1 548

462.60 463.9 0.52 B1 549

475.60 476.4 1.15 QC- ACN- AA-XB 550

459.60 460 1.4 QC- ACN- AA-XB 551

473.63 474 0.53 B1 552

480.63 481.3 0.53 B1 553

413.53 414.3 0.63 B1 554

496.63 497.3 0.56 B1 555

429.53 430.9 0.58 B1 556

494.66 495.3 0.6 B1 557

427.56 428.3 0.66 B1 558

447.54 448 1.12 QC- ACN- AA-XB 559

431.54 432.4 0.67 QC- ACN- AA-XB 560

445.57 446 1.16 QC- ACN- AA-XB 561

471.61 471.9 0.53 B1 562

487.61 487.9 0.51 B1 563

485.64 485.9 0.52 B1 564

483.05 471.9 0.53 B1 565

470.01 470.3 1.46 QC- ACN- AA-XB 566

455.00 455.4 0.71 QC- ACN- TFA- XB 567

484.04 484.5 0.74 QC- ACN- TFA- XB 568

441.02 441.1 1.39 QC- ACN- AA-XB 569

455.04 455.15 0.84 QC- ACN- TFA- XB 570

484.04 483.9 0.53 B1 571

471.04 471.9 0.54 B1 572

460.63 461.2 1.6 E 573

514.62 515.2 2.14 E 574

464.55 465.2 1.66 E 575

472.64 473.2 1.5 E 576

489.62 490.2 1.52 E 577

493.59 494.1 1.85 E 578

444.58 445.2 1.94 E 579

460.58 461.2 1.88 E 580

477.59 478.3 1.4 E 581

473.63 474.2 1.54 E 582

498.62 499.3 1.63 E 583

493.59 494.3 1.36 E 584

489.62 490.2 1.5 E 585

477.59 478.2 1.89 E 586

473.63 474.2 1.55 E 587

476.63 477.2 1.56 E 588

448.55 449.3 1.71 E 589

488.64 489.2 1.46 E 590

434.54 435.4 0.94 QC- ACN- TFA- XB 591

504.64 505.5 1.23 QC- ACN- AA-XB 592

434.54 435.2 1.08 QC- ACN- TFA- XB 593

448.57 448.9 1.3 QC- ACN- AA-XB 594

404.52 405.4 1.01 QC- ACN- TFA- XB 595

462.55 463.3 1.31 QC- ACN- AA-XB 596

392.46 393.2 1 QC- ACN- TFA- XB 597

492.62 493.6 1.28 QC- ACN- AA-XB 598

462.60 463 1.22 QC- ACN- TFA- XB 599

464.57 465.2 1.11 QC- ACN- TFA- XB 600

420.52 421.2 1.17 QC- ACN- AA-XB 601

337.38 338 0.77 B1 602

505.62 506.2 1.01 QC- ACN- TFA- XB 603

448.57 449 1.22 QC- ACN- AA-XB 604

526.66 527.5 0.98 QC- ACN- TFA- XB 605

504.68 505.5 1.51 QC- ACN- AA-XB 606

462.60 462.9 1.51 QC- ACN- AA-XB 607

490.61 491.2 1.33 QC- ACN- AA-XB 608

406.49 407.3 0.96 QC- ACN- TFA- XB 609

491.60 492 1.28 QC- ACN- AA-XB 610

448.57 449.4 1.11 QC- ACN- AA-XB 611

504.68 505.5 1.3 QC- ACN- TFA- XB 612

420.52 421 1.4 QC- ACN- AA-XB 613

478.60 479.2 1.2 QC- ACN- AA-XB 614

448.57 449.4 0.99 QC- ACN- TFA- XB 615

473.63 474.25 1.31 QC- ACN- AA-XB 616

460.58 461.3 1.38 QC- ACN- AA-XB 617

374.49 375 0.7 QC- ACN- TFA- XB 618

402.55 403.2 0.99 QC- ACN- TFA- XB 619

461.57 462.2 1.24 QC- ACN- AA-XB 620

376.46 377.4 0.96 QC- ACN- AA-XB 621

494.66 495.2 0.77 QC- ACN- TFA- XB 622

473.63 474.1 0.98 QC- ACN- TFA- XB 623

402.55 402.9 0.72 QC- ACN- TFA- XB 624

480.63 481.4 1.19 QC- ACN- AA-XB 625

475.60 476.3 1.22 QC- ACN- AA-XB 626

472.64 473.2 0.78 QC- ACN- TFA- XB 627

475.60 476.2 0.73 QC- ACN- TFA- XB 628

447.54 448.2 0.67 QC- ACN- TFA- XB 629

404.52 405 1.1 QC- ACN- AA-XB 630

475.60 476.4 0.74 QC- ACN- TFA- XB 631

445.57 446.2 1.19 QC- ACN- AA-XB 632

460.58 461.2 1.19 QC- ACN- AA-XB 633

542.73 543.3 1.04 QC- ACN- TFA- XB 634

482.60 483 1.22 QC- ACN- AA-XB 635

458.61 459.22 1.23 QC- ACN- AA-XB 636

494.66 495.2 1.54 QC- ACN- AA-XB 637

458.61 459.1 1.43 QC- ACN- AA-XB 638

461.57 462.4 0.74 QC- ACN- TFA- XB 639

404.52 405 1.12 QC- ACN- AA-XB 640

496.63 497.1 1.42 QC- ACN- AA-XB 641

460.63 461.1 0.78 QC- ACN- AA-XB 642

496.63 497.1 1.47 QC- ACN- AA-XB 643

474.61 475.3 0.71 QC- ACN- TFA- XB 644

459.60 460.5 1.2 QC- ACN- AA-XB 645

419.49 420.3 0.93 QC- ACN- AA-XB 646

417.52 418.4 0.96 QC- ACN- AA-XB 647

468.58 469.4 0.78 QC- ACN- TFA- XB 648

362.44 363.3 0.65 QC- ACN- TFA- XB 649

360.47 361.3 0.69 QC- ACN- TFA- XB 650

445.57 446 0.98 QC- ACN- TFA- XB 651

443.52 444.4 0.74 QC- ACN- TFA- XB 652

447.54 448.4 0.68 QC- ACN- TFA- XB 653

466.60 467.4 0.8 QC- ACN- TFA- XB 654

432.57 433.4 0.84 QC- ACN- TFA- XB 655

404.52 405.2 1.2 QC- ACN- AA-XB 656

402.55 403.3 0.89 QC- ACN- TFA- XB 657

434.54 435.41 0.83 QC- ACN- TFA- XB 658

432.57 433.2 1.48 QC- ACN- AA-XB 659

476.58 477.4 1.42 QC- ACN- AA-XB 660

434.54 435.1 1.02 QC- ACN- TFA- XB 661

406.49 407.3 1.26 QC- ACN- AA-XB 662

390.49 391.2 0.99 QC- ACN- AA-XB 663

475.60 476.2 0.79 QC- ACN- TFA- XB 664

474.61 475.3 1.41 QC- ACN- AA-XB 665

380.49 381.1 1.34 QC- ACN- AA-XB 666

392.46 393.2 0.75 QC- ACN- TFA- XB 667

422.53 423.2 0.75 QC- ACN- TFA- XB 668

477.57 478.3 1.06 QC- ACN- AA-XB 669

366.47 367.1 0.86 QC- ACN- AA-XB 670

405.50 406.3 1.38 QC- ACN- AA-XB 671

392.46 393.1 0.97 QC- ACN- AA-XB 672

491.60 492.3 1.06 QC- ACN- AA-XB 673

404.52 405.2 1.2 QC- ACN- AA-XB 674

496.63 497.3 1.35 QC- ACN- AA-XB 675

366.47 367 0.77 QC- ACN- TFA- XB 676

392.46 393.3 0.76 QC- ACN- TFA- XB 677

451.57 452.2 0.95 QC- ACN- AA-XB 678

408.55 409.3 0.82 QC- ACN- TFA- XB 679

366.47 367.2 0.97 QC- ACN- AA-XB 680

389.51 390.1 1.13 QC- ACN- AA-XB 681

402.55 403.1 1.24 QC- ACN- AA-XB 682

418.55 419.4 0.77 QC- ACN- TFA- XB 683

458.61 458.9 1.31 QC- ACN- AA-XB 684

479.64 480.1 1.47 QC- ACN- AA-XB 685

473.63 474.3 1.49 QC- ACN- AA-XB 686

444.58 445.2 0.92 QC- ACN- AA-XB 687

444.58 445.1 0.73 QC- ACN- TFA- XB 688

471.57 472.2 1 QC- ACN- AA-XB 689

475.60 475.9 1.28 QC- ACN- AA-XB 690

373.50 374.1 0.84 QC- ACN- TFA- XB 691

457.62 457.9 1.64 QC- ACN- AA-XB 692

388.52 389.1 0.72 QC- ACN- TFA- XB 693

462.60 463 1.29 QC- ACN- AA-XB 694

429.57 430.2 0.71 QC- ACN- TFA- XB 695

494.66 495.4 1.14 QC- ACN- AA-XB 696

473.63 474.37 1.07 QC- ACN- AA-XB 697

390.49 391.3 0.95 QC- ACN- AA-XB 698

496.63 497.3 1.09 QC- ACN- AA-XB 699

475.60 476.4 0.76 QC- ACN- TFA- XB 700

446.56 447.3 1.08 QC- ACN- AA-XB 701

460.63 461.4 1.1 QC- ACN- AA-XB 702

472.64 473.4 1.12 QC- ACN- AA-XB 703

458.61 459.4 1.2 QC- ACN- AA-XB 704

454.58 454.9 1.35 QC- ACN- AA-XB 705

469.60 470.47 0.74 QC- ACN- TFA- XB 706

474.61 475.4 1.1 QC- ACN- AA-XB 707

474.61 475.4 1.27 E 708

504.60 505 1.26 E 709

496.63 497 1.05 E 710

474.61 475.3 1.27 E 711

474.61 475.3 1.33 E 712

475.60 476.3 1.55 E 713

468.57 469 1.8 E 714

515.66 516.4 1.35 E 715

446.56 447.3 1.43 E 716

429.53 430.3 1.94 E 717

602.77 603.3 1.34 E 718

474.61 475.4 1.34 E 719

461.57 462.3 1.29 E 720

504.60 505.3 1.26 E 721

474.61 475 1.27 E 722

560.70 561 1.5 E 723

432.57 433.3 1.32 E 724

458.61 459.3 1.46 E 725

461.57 462.3 1.3 E 726

602.77 603 1.34 E 727

474.61 475.4 1.38 E 728

474.61 475.3 1.35 E 729

502.66 503.3 1.41 E 730

468.57 469 1.8 E 731

489.62 490.1 1.34 E 732

449.56 450.1 1.19 E 733

475.55 476.1 1.29 E 734

474.49 475.1 1.86 E 735

440.56 441.2 1.32 QC- ACN- AA-XB 736

470.58 470.9 1.57 QC- ACN- AA-XB

Example 7376-(5-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 737A: tert-butyl5-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A suspension of tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(600 mg, 1.24 mmol), tert-butyl(2R,5S)-2,5-dimethylpiperazine-1-carboxylate, HCl (466 mg, 1.86 mmol),Pd₂(dba)₃ (113 mg, 0.124 mmol),dicyclohexyl(2′,6′-di-isopropoxy-[1,1′-biphenyl]-2-yl)phosphine (69.4mg, 0.149 mmol), and Cs₂CO₃ (1.82 g, 5.57 mmol) in 1,4-dioxane (12.5 mL)in a reaction vial with a pressure-relief septum-lined cap and a stirbar was degassed with nitrogen gas for 5 minutes. The reaction vial wassealed and placed in a heating block with stirring at 105° C. for 6.5hours, then cooled to room temperature, and remained at room temperatureovernight. The reaction was then restarted by the addition of tert-butyl(2R,5S)-2,5-dimethylpiperazine-1-carboxylate, HCl (233 mg, 0.93 mmol),Pd₂(dba)₃ (57 mg, 0.062 mmol),dicyclohexyl(2′,6′-di-isopropoxy-[1,1′-biphenyl]-2-yl)phosphine (35 mg,0.075 mmol), and Cs₂CO₃ (908 mg, 2.79 mmol), degassed with nitrogen gas,and heated to 105° C. with stirring for 4 hours more. Upon completion,the reaction mixture was cooled to room temperature and remained at roomtemperature overnight. The reaction mixture was then filtered,concentrated, and taken up in DCM. The crude material was purified bysilica gel column chromatography on a Teledyne Isco instrument elutingin Hex/EtOAc 0-100% to afford tert-butyl5-(2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(698 mg, 1.130 mmol, 91% yield). LCMS retention time 1.26 [TS]. MS (E⁺)m/z: 618.7 (M+H).

Example 737

tert-Butyl5-(2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(698 mg, 1.13 mmol) was suspended in TFA (6 mL) at room temperature andstirred for 3 hours. The reaction mixture was then concentrated,redissolved in CHCl₃/iPrOH 3/1 and neutralized with 1.5M aqueous K₂HPO₄solution in a separatory funnel. The organic layer was separated, driedover sodium sulfate, filtered, and concentrated to afford materialconsidered to be quantitative of6-(5-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(1.13 mmol).

For characterization purposes, a portion of the crude product from aseparate preparation of6-(5-(2S,5R)-2,5-dimethylpiperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridinerun on smaller scale was purified by preparative LC/MS using thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C.Fraction collection was triggered by MS and UV signals. The fractionscontaining the product were combined and dried via centrifugalevaporation to afford6-(5-(2S,5R)-2,5-dimethylpiperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (15.5 mg). LCMS retention time 0.93 [QC-ACN-TFA-XB]. MS (E⁺) m/z:418.5 (M+H). Select NMR peaks: ¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s,1H), 9.03 (br s, 1H), 8.78 (s, 2H), 8.47 (s, 1H), 7.64 (br d, J=8.9 Hz,1H), 6.82 (br d, J=8.5 Hz, 1H), 4.18-4.04 (m, 1H), 3.67-3.53 (m, 1H),3.45-3.33 (m, 1H), 3.11-2.97 (m, 1H), 2.86-2.75 (m, 1H), 2.59 (s, 3H),2.17 (s, 3H), 1.42-1.35 (m, 6H), 1.29 (br d, J=6.4 Hz, 3H), 1.16 (br d,J=6.4 Hz, 3H).

Example 7381(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)-2-(pyrrolidin-1-yl)ethan-1-one

Intermediate 738A:2-chloro-1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)ethan-1-one

6-(5-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.496 mmol) was suspended in DCM (4 mL). Et₃N (0.346 mL, 2.48 mmol) and2-chloroacetyl chloride (0.079 mL, 0.992 mmol) were added sequentially.The reaction mixture was stirred at room temperature for 30 minutes.Another aliquot of 2-chloroacetyl chloride (0.025 mL, 0.314 mmol) wasadded. The reaction mixture was stirred for an additional 2 minutes. Thereaction was quenched by addition of water, DCM, and 1.5 M aqueousK₂HPO₄ solution. The layers were separated, and the aqueous layer wasextracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated to afford crude material which wasconsidered quantitative recovery of2-chloro-1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)ethan-1-one(0.496 mmol). LCMS retention time 0.70 [TS]. MS (E+) m/z: 494.4 (M+H).

Example 738

2-Chloro-1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)ethan-1-one(0.0496 mmol) was suspended in DMF (1 mL). Pyrrolidine (0.050 mL, 0.609mmol) was added, and the reaction mixture was stirred for 19 hours atroom temperature. Upon completion, the reaction mixture was diluted witha few drops of water, DMF, filtered, and purified by preparative LC/MSvia the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 16% B, 16-56% B over 20 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS signals. Thefractions containing the product were combined and dried via centrifugalevaporation to afford1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)-2-(pyrrolidin-1-yl)ethan-1-one(14.2 mg, 0.027 mmol, 54.1% yield). LCMS retention time 1.46[QC-ACN-AA-XB]. MS (E⁺) m/z: 529.5 (M+H). Select NMR peaks (rotamerspresent): ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.70 (br s, 1H),8.45 (s, 1H), 7.54 (d, J=8.9 Hz, 1H), 6.71 (br dd, J=8.8, 6.0 Hz, 1H),2.80-2.72 (m, 1H), 2.56 (s, 3H), 2.15 (s, 3H), 1.76-1.61 (m, 4H), 1.36(br d, J=5.8 Hz, 6H), 1.29-0.93 (m, 6H).

Example 7391-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one

Intermediates 739A and 739B:3-chloro-1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)propan-1-oneand14(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one

6-(5-(2S,5R)-2,5-dimethylpiperazin-1-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.496 mmol) was suspended in DCM (4 mL). Et₃N (0.35 mL, 2.48 mmol) and3-chloropropanoyl chloride (0.095 mL, 0.992 mmol) were addedsequentially and the reaction mixture was stirred for 15 minutes at roomtemperature. Upon completion, the reaction was quenched. The reactionmixture was worked up by dilution with water, DCM, and 1.5M aqueousK₂HPO₄ solution. The organic layer was separated and the aqueous layerwas extracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated to afford crude material which wascarried into the next steps as is and considered quantitative recoveryof both materials (0.496 mmol total) as a mixture of an unidentifiedratio of3-chloro-1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)propan-1-one(LCMS retention time 0.72 [TS]. MS (E+) m/z: 508.5 (M+H)) and1-((2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one(LCMS retention time 0.68 [TS]. MS (E⁺) m/z: 472.5 (M+H).

Example 739

A mixture of3-chloro-1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)propan-1-oneand1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one(0.0413 mmol) was suspended in DMF (1 mL). Pyrrolidine (0.05 mL, 0.609mmol) was added and the reaction mixture was stirred at room temperaturefor 20 hours. Upon completion, the reaction mixture was diluted with afew drops of water, DMF, filtered, and purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 15% B, 15-55% B over 20 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25 C. Fraction collection was triggered by MS signals. Thefractions containing the product were combined and dried via centrifugalevaporation to afford 1-(2R,5S)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,5-dimethylpiperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one(18.0 mg, 0.032 mmol, 78% yield). LCMS retention time 1.07[QC-ACN-TFA-XB]. MS (E⁺) m/z: 543.4 (M+H). Select NMR peaks (rotamerspresent): ¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.73 (br s, 1H),8.47-8.44 (m, 1H), 7.54 (d, J=9.0 Hz, 1H), 6.76-6.67 (m, 1H), 2.81-2.62(m, 3H), 2.57 (s, 3H), 2.16 (s, 3H), 1.68 (br d, J=2.8 Hz, 4H), 1.37 (brd, J=6.6 Hz, 6H), 1.30-0.94 (m, 6H).

Example 7406-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 740A: tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A suspension of tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(150 mg, 0.310 mmol), tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.5 oxalic acid salt (113 mg,0.464 mmol), 2^(nd) generation RuPhos precatalyst (11 mg, 0.014 mmol),and Cs₂CO₃ (353 mg, 1.084 mmol) in 1,4-dioxane (3.1 mL) was degassedwith nitrogen for 5 minutes in a reaction vial with a pressure-reliefseptum-lined cap. The reaction vial was sealed and placed in a heatingblock at 100° C. with stirring. After 2 hours, more RuPhos 2^(nd)generation precatalyst (27 mg, 0.035 mmol) was added, the suspension wasfurther degassed, and the reaction mixture was taken back up to 100° C.with stirring for 2 hours. Upon completion, the reaction mixture wasfiltered, concentrated, and purified by Silica gel column chromatographyeluting with Hex/EtOAc 0-100% to afford tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(124 mg, 66.5% yield) containing some co-eluting impurities. LCMSretention time 0.99 [TS]. MS (E⁺) m/z: 602.3 (M+H).

Example 740

A solution of tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(124 mg, 0.206 mmol) in TFA (3 mL) was stirred at room temperature for 2hours. Upon completion, the reaction mixture was concentrated andconsidered quantitative recovery of6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (0.206 mmol). 90% of this material was carried on as is. 10% of thismaterial was purified by preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractionscontaining the product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25 C. Fraction collection was triggered by MS signals. Thefractions containing the product were combined and dried via centrifugalevaporation to afford6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(3.1 mg, 0.0075 mmol). LCMS retention time 1.21 [QC-ACN-AA-XB]. MS (E⁺)m/z: 402.0 (M+H). Select NMR peaks: ¹H NMR (500 MHz, DMSO-dc) δ 10.85(s, 1H), 8.75 (s, 1H), 8.46 (s, 1H), 7.52 (br d, J=8.5 Hz, 1H), 6.28 (brd, J=8.9 Hz, 1H), 4.00 (s, 4H), 2.84-2.77 (m, 1H), 2.16 (s, 3H), 1.36(br d, J=6.7 Hz, 6H).

Example 7416-(3-isopropyl-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (15.93 mg, 0.0309 mmol) and Et₃N (0.05 mL, 0.359 mmol) were mixed inDMF (1 mL). Formaldehyde (37% wt in water, 25 μL, 0.336 mmol) was addedto the reaction vial followed by sodium triacetoxyborohydride (54 mg,0.255 mmol). The reaction mixture was stirred at room temperature for 90minutes. Upon completion, the reaction was quenched by the addition ofwater, 1.5 M aqueous K₂HPO₄ solution, and DCM. The organic layer wasseparated and concentrated. The crude material was dissolved in DMF forpurification via preparative LC/MS with the following conditions:Column: XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 1% B, 1-41% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. The fractions containing the product werecombined and dried via centrifugal evaporation to afford6-(3-isopropyl-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(3.2 mg, 7.70 μmol, 25% yield). LCMS retention time 1.29 [QC-ACN-AA-XB].MS (E⁺) m/z: 415.9 (M+H). Select NMR peaks: ¹H NMR (500 MHz, DMSO-d₆) δ10.82 (s, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 6.26(d, J=8.5 Hz, 1H), 3.96 (s, 4H), 2.84-2.75 (m, 1H), 2.57 (s, 3H), 2.22(s, 3H), 2.14 (s, 3H), 1.34 (br d, J=6.7 Hz, 6H).

Example 7422-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-N,N-dimethylacetamide

6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (15.93 mg, 0.0309 mmol) and DBU (0.05 mL, 0.332 mmol) were mixed inDMF (1 mL). Excess 2-chloro-N,N-dimethylacetamide (approximately 184)was added to the reaction vial and the mixture was stirred for 1.5hours. Upon completion, the reaction mixture was diluted with a fewdrops of water, DMF, and the crude material was purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 200 mm×19 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mMammonium acetate; Gradient: a 0-minute hold at 10% B, 10-50% B over 20minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25 C. Fraction collection was triggered by MS signals. Thefractions containing the product were combined and dried via centrifugalevaporation to afford2-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-N,N-dimethylacetamide(6.6 mg, 0.013 mmol, 43.6% yield). LCMS retention time 1.33[QC-ACN-AA-XB]. MS (E⁺) m/z: 486.9 (M+H). Select NMR peaks: ¹H NMR (500MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 7.51 (d,J=8.5 Hz, 1H), 6.27 (d, J=8.5 Hz, 1H), 2.58 (s, 3H), 2.15 (s, 3H), 1.35(br d, J=6.4 Hz, 6H).

Example 7431-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(dimethylamino)ethan-1-one

A solution of6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine,TFA (15.93 mg, 0.0309 mmol) in methanol was converted to the HCl saltform by adding 1 mL of 4 N HCl in dioxane and concentrating to dryness.The material was taken up in methanol a second time, 1 mL of 4N HCl indioxane was again added, and the material was concentrated to dryness.The material was then suspended in DMF (1 mL) and N,N-dimethylglycine(20 mg, 0.194 mmol), Et₃N (0.1 mL, 0.717 mmol), and T3P (50% in DMF,0.090 mL, 0.155 mmol) were added sequentially at room temperature withstirring. After 1.5 hours, another aliquot of N,N-dimethylglycine (9 mg,0.087 mmol), Et₃N (0.1 mL, 0.717 mmol), and T3P (50% in DMF, 0.090 mL,0.155 mmol) were added and the reaction mixture was stirred for 26 hoursat room temperature. Upon completion, the reaction was quenched by theaddition of water, 1.5 M aqueous K₂HPO₄ solution, and DCM. The organiclayer was separated, concentrated, and the crude isolate was dilutedwith DMF. The crude material was purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate;Gradient: a 0-minute hold at 16% B, 16-56% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS signals. Fractions containingthe product were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: XBridge Phenyl, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 12% B, 12-52% B over 25 minutes, then a 6-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractioncollection was triggered by MS signals. The fractions containing theproduct were combined and dried via centrifugal evaporation to afford1-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(dimethylamino)ethan-1-one(2.5 mg, 5.03 μmol, 16% yield). LCMS retention time 1.17 [QC-ACN-AA-XB].MS (E⁺) m/z: 487.1 (M+H). NMR (500 MHz, DMSO-d₆) δ10.85 (s, 1H), 8.72(s, 1H), 8.45 (s, 1H), 7.53 (br d, J=8.9 Hz, 1H), 6.29 (br d, J=8.5 Hz,1H), 4.35 (s, 2H), 4.07 (br s, 2H), 4.04 (s, 4H), 2.90 (s, 2H),2.84-2.74 (m, 1H), 2.57 (s, 3H), 2.17 (s, 6H), 2.14 (s, 3H), 1.34 (br d,J=6.4 Hz, 6H).

Example 7446-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Alternate synthesis of Intermediate 740A: tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A suspension of tert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(332 mg, 0.685 mmol), Pd₂(dba)₃ (62.8 mg, 0.069 mmol),dicyclohexyl(2′,6′-di-isopropoxy-[1,1′-biphenyl]-2-yl)phosphine (38.4mg, 0.082 mmol), and Cs₂CO₃ (902 mg, 2.77 mmol) in 1,4-dioxane (6.9 mL)in a vial with a pressure-relief septum-lined cap and stir bar wasdegassed with nitrogen for 5 minutes. The mixture was sealed and placedin a heating block at 105° C. with stirring for 7 hrs and then remainedat room temperature overnight. The reaction mixture was filtered,concentrated, and purified by silica gel column chromatography elutingwith Hex/EtOAc 0-100% to afford tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.685 mmol) considered to be quantitative recovery.

Alternate Synthesis of Example 740:6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

A solution of tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(0.685 mmol) in TFA (3.5 mL) at room temperature was stirred for 2hours. Upon completion, the material was concentrated, taken up in 3/1CHCl₃/iPrOH and neutralized by mixing with 1.5 M aqueous K₂HPO₄ solutionand water in a separatory funnel. The aqueous layer was extracted with3/1 CHCl₃/iPrOH. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated to afford crude material, consideredquantitative recovery of6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.685 mmol). LCMS retention time 0.53 [TS]. MS (E⁺) m/z: 402.3 (M+H).

Intermediate 744A:1-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one

To a stirred suspension of6-(3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.173 mmol) in DCM (3 mL) were sequentially added Et₃N (0.121 mL, 0.865mmol) and acetic anhydride (0.025 mL, 0.260 mmol). After 10 minutes, thereaction mixture was concentrated to afford crude material. Thismaterial was purified by silica gel column chromatography on a TeledyneIsco instrument eluting with Hex/EtOAc 0-100% then DCM/MeOH 0-10% toafford1-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one(66 mg, 0.149 mmol, 86% yield). LCMS retention time 0.60 [TS]. MS (E⁺)m/z: 444.5 (M+H).

Example 744

To a stirred solution of1-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one(66 mg, 0.149 mmol) in THF (3 mL) was added LiAlH₄ (17 mg, 0.446 mmol),and the vial was sealed at room temperature. After 90 minutes, thereaction was quenched by the addition of DCM and 1.5 M aqueous K₂HPO₄solution. The organic layer was separated and the aqueous layer wasextracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated. The obtained crude material wastaken up in DMF and purified by preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×30 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 9% B, 9-49% B over 20 minutes, then a 2-minute holdat 100% B; Flow Rate: 45 mL/min; Column Temperature: 25° C. Fractioncollection was triggered by MS and UV signals. Fractions containing theproduct were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 8% B, 8-48% B over 20 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fractioncollection was triggered by MS and UV signals. The fractions containingthe product were combined and dried via centrifugal evaporation toafford 6-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-3-isopropyl-1Hpyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(43.4 mg, 0.100 mmol, 67.5% yield). LCMS retention time 1.31[QC-ACN-AA-XB]. MS (E⁺) m/z: 430.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ10.83 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.53 (d, J=8.9 Hz, 1H), 6.28(d, J=8.5 Hz, 1H), 3.99 (s, 4H), 2.83-2.75 (m, 1H), 2.68-2.59 (m, 2H),2.55 (s, 3H), 2.12 (s, 3H), 1.32 (br d, J=6.4 Hz, 6H), 0.93 (br t, J=7.0Hz, 3H).

Example 7456-(3-isopropyl-5-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 745A: tert-butyl6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.0 g, 9.38 mmol) in DCM(45 mL) at room temperature was added Et₃N (3.27 mL, 23.4 mmol) and MsCl(1.1 mL, 14.1 mmol) sequentially. After 3.25 hours, the reaction wasquenched by the addition of water and DCM. The layers were separated andthe aqueous layer was extracted with DCM. The combined organic layer wasdried over sodium sulfate, filtered, and concentrated to afford crudematerial considered to be quantitative of tert-butyl6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (9.38 mmol,100% yield).

Intermediate 745B: tert-butyl6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

tert-Butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate(4.69 mmol) was suspended in ethyl methyl ketone (19 mL) and sodiumiodide (3.52 g, 23.5 mmol) was added. The mixture was degassed withnitrogen gas for 10 minutes, then the reaction vial sealed with apressure-relief septum-lined cap and heated to 100° C. with stirring for19.75 hours. An identical reaction was set up in duplicate and run inparallel. Upon completion, the reaction mixtures were cooled to roomtemperature and quenched by the addition of water and DCM. The parallelreaction mixtures were combined for workup. The layers were separated,and the aqueous layer was extracted with DCM. The combined organic layerwas dried over sodium sulfate, filtered, and concentrated to afford acrude oil. This material was dissolved in DCM and purified on silica gelcolumn chromatography on a Teledyne Isco instrument eluting withHex/EtOAc 0-60%. The fractions containing the material were concentratedand repurified as above eluting with Hex/EtOAc 0-40% to give tert-butyl6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (2.1 g) total combined fromboth parallel runs as a white solid. ¹H NMR (499 MHz, CHLOROFORM-d) δ4.29 (quin, J=7.8 Hz, 1H), 3.95 (s, 2H), 3.92 (s, 2H), 2.97-2.87 (m,2H), 2.75-2.66 (m, 2H), 1.42 (s, 9H).

Intermediate 745C: tert-butyl5-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

In a 100-mL round-bottom flask with a stir bar, a suspension oftert-butyl5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.57 g, 3.25 mmol), tert-butyl6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (2.1 g, 6.50 mmol),tris(trimethylsilyl)silane (1.21 g, 4.87 mmol),[Ir(dF(CF₃)ppy)₂(dtbbpy)]PF₆ (0.036 g, 0.032 mmol), and Na₂CO₃ (1.38 g,13.0 mmol) in 1,4-dioxane (30 mL) was degassed through a rubber septumwith a line of nitrogen gas for 15 minutes. To a vial with a stir barwas added nickel(II) chloride ethylene glycol dimethyl ether complex(0.018 g, 0.081 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (0.026 g,0.097 mmol), which was purged with nitrogen gas. 1,4-Dioxane (6 mL) wasadded and the resulting mixture was degassed with nitrogen gas for 10minutes and stirred. The resulting solution was then added to thereaction flask. The resulting mixture was further degassed with nitrogengas for another 15 minutes, and then the nitrogen gas line was removedand a nitrogen balloon was affixed to the flask via a needle through theseptum. The reaction vessel was secured over a stir plate with stirring,a cooling fan, and irradiation from 34 W Kessil KSH 150B blue grow lamps(12 cm apart, flask in between) for 66 hours. Upon completion, thereaction mixture was filtered, concentrated, and redissolved in DCM. Thematerial was purified by silica gel column chromatography on a TeledyneIsco instrument eluting with Hex/EtOAc 0-60% to afford tert-butyl5-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(1.27 g, 2.11 mmol, 65.1% yield) containing a small amount of co-elutingimpurities. LCMS retention time 1.13 [TS]. MS (E⁺) m/z: 601.7 (M+H). ¹HNMR (499 MHz, CHLOROFORM-d) δ 8.35 (s, 1H), 8.34 (d, J=8.6 Hz, 1H), 8.33(s, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.05 (s, 2H), 3.96 (s, 2H), 3.60 (quin,J=8.1 Hz, 1H), 2.86-2.77 (m, 1H), 2.66 (s, 3H), 2.65-2.56 (m, 4H), 2.13(s, 3H), 1.46-1.41 (m, 15H), 1.22 (s, 9H).

Example 745

A solution of tert-butyl5-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(584 mg, 0.972 mmol) in TFA (6 mL) was stirred for 2 hours at roomtemperature. Upon completion, the reaction mixture was concentrated anddissolved in 3/1 CHCl₃/iPrOH. This organic layer was neutralized bymixing in a separatory funnel with 1.5 M aqueous K₂HPO₄ solution. Theaqueous layer was extracted with 3/1 CHCl₃/iPrOH, and the combinedorganic layer was dried over sodium sulfate, filtered, and concentratedto afford material considered to be quantitative recovery of6-(3-isopropyl-5(2-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.972 mmol). The majority of this material was carried forward as is. Aportion (5%) of this material was purified by preparative LCMS using thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate;Gradient: a 0-minute hold at 5% B, 5-45% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractionscontaining the product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 5% B, 5-55% B over 20 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS signals. Thefractions containing the product were combined and dried via centrifugalevaporation to afford6-(3-isopropyl-5-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(4.5 mg, 0.0106 mmol). LCMS retention time 1.05 [QC-ACN-TFA-XB]. MS (E⁺)m/z: 401.3 (M+H). Select NMR peaks: ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s,1H), 8.46 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H),2.93-2.83 (m, 1H), 2.58 (s, 3H), 2.15 (s, 3H), 1.39 (br d, J=6.7 Hz,6H).

Example 7461-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-2-yl)-3-(dimethylamino)propan-1-one

To a solution of6-(3-isopropyl-5-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(19.5 mg, 0.0486 mmol), 3-(dimethylamino)propanoic acid (18 mg, 0.154mmol), and Et₃N (0.05 mL, 0.359 mmol) in DMF (1 mL) was added T3P (0.057mL, 0.097 mmol). The mixture was stirred at room temperature for 1.5hours. Upon completion, the reaction was quenched. The reaction mixturewas worked up by the addition of water, 1.5 M aqueous K₂HPO₄ solution,and DCM. The organic layer was separated, concentrated, and diluted withDMF. The material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 10% B, 10-50% B over 25 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractioncollection was triggered by MS signals. Fractions containing the productwere combined and dried via centrifugal evaporation to afford1-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-2-yl)-3-(dimethylamino)propan-1-one(6.2 mg, 0.012 mmol, 24% yield). LCMS retention time 1.31[QC-ACN-AA-XB]. MS (E⁺) m/z: 500.3 (M+H). Select NMR peaks, rotamerspresent: ¹H NMR (500 MHz, DMSO-d₆) δ11.13 (br s, 1H), 8.80 (s, 1H), 8.47(s, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.97 (br d, J=8.5 Hz, 1H), 4.25 (s,1H), 4.17 (s, 1H), 3.96 (s, 1H), 3.84 (s, 1H), 3.62-3.52 (m, 1H),2.94-2.86 (m, 1H), 2.59 (s, 3H), 2.16 (s, 6H), 2.14 (s, 3H), 1.47-1.37(m, 6H).

The following examples were prepared according to the general proceduresdescribed in the above examples.

TABLE 2 Obs. Ex. MS QC No. Structure Ion RT Method 737

418.40 1.26 QC- ACN- AA-XB 738

529.30 0.89 QC- ACN- TFA- XB 739

543.40 1.07 QC- ACN- TFA- XB 740

402.30 0.97 QC- ACN- TFA- XB 741

415.90 1.29 QC- ACN- AA-XB 742

487.20 0.96 QC- ACN- TFA- XB 743

486.90 0.99 QC- ACN- TFA- XB 744

430.10 1.21 QC- ACN- AA-XB 745

401.30 1.04 QC- ACN- TFA- XB 746

500.30 1.31 QC- ACN- AA-XB 747

501.50 1.45 QC- ACN- AA-XB 748

522.30 1.17 QC- ACN- TFA- XB 749

487.20 1.55 QC- ACN- AA-XB 750

515.40 1.02 QC- ACN- TFA- XB 751

536.20 2.02 QC- ACN- AA-XB 752

503.40 1.42 QC- ACN- AA-XB 753

489.40 0.87 QC- ACN- TFA- XB 754

487.10 1.53 QC- ACN- AA-XB 755

444.20 1.33 QC- ACN- AA-XB 756

473.40 1.16 QC- ACN- AA-XB 757

418.20 1.22 QC- ACN- AA-XB 758

489.00 1.38 QC- ACN- AA-XB 759

475.20 1.73 QC- ACN- AA-XB 760

503.30 0.84 QC- ACN- TFA- XB 761

517.30 0.87 QC- ACN- TFA- XB 762

459.40 0.76 QC- ACN- TFA- XB 763

472.90 1.33 QC- ACN- AA-XB 764

508.10 0.98 QC- ACN- TFA- XB 765

522.50 0.81 QC- ACN- TFA- XB 766

440.90 1.76 QC- ACN- AA-XB 767

501.20 1.49 QC- ACN- AA-XB 768

458.10 0.96 QC- ACN- TFA- XB 769

243.60 1.44 QC- ACN- AA-XB 770

534.10 1.64 QC- ACN- AA-XB 771

470.10 1.66 QC- ACN- AA-XB 772

244.00 1.50 QC- ACN- AA-XB 773

501.20 1.48 QC- ACN- AA-XB 774

459.10 1.58 QC- ACN- AA-XB 775

473.40 1.20 QC- ACN- AA-XB 776

501.00 1.42 QC- ACN- AA-XB 777

508.40 0.99 QC- ACN- TFA- XB 778

522.20 1.40 QC- ACN- AA-XB 779

458.10 0.98 QC- ACN- TFA- XB 780

486.20 1.43 QC- ACN- AA-XB 781

534.40 0.98 QC- ACN- TFA- XB 782

236.30 0.99 QC- ACN- TFA- XB 783

444.40 1.40 QC- ACN- AA-XB 784

487.50 1.33 QC- ACN- AA-XB 785

501.50 0.82 QC- ACN- TFA- XB 786

444.20 0.81 QC- ACN- TFA- XB 787

497.30 0.80 QC- ACN- TFA- XB 788

503.00 1.13 QC- ACN- TFA- XB 789

517.40 0.92 QC- ACN- TFA- XB 790

503.40 0.84 QC- ACN- TFA- XB 791

475.30 0.80 QC- ACN- TFA- XB 792

446.20 1.15 QC- ACN- TFA- XB 793

460.30 1.10 QC- ACN- TFA- XB 794

489.30 0.98 QC- ACN- TFA- XB 795

538.30 1.00 QC- ACN- TFA- XB 796

503.30 1.49 QC- ACN- AA-XB 797

517.40 0.95 QC- ACN- TFA- XB 798

489.00 0.86 QC- ACN- TFA- XB 799

475.20 0.88 QC- ACN- TFA- XB 800

475.20 0.86 QC- ACN- TFA- XB 801

489.50 1.36 QC- ACN- AA-XB 802

476.20 1.70 QC- ACN- AA-XB 803

489.60 1.69 QC- ACN- AA-XB 804

475.10 0.76 QC- ACN- TFA- XB 805

524.50 0.71 QC- ACN- TFA- XB 806

524.10 1.05 QC- ACN- TFA- XB 807

474.90 1.49 QC- ACN- AA-XB 808

489.50 1.44 QC- ACN- AA-XB 809

461.10 1.58 QC- ACN- AA-XB 810

443.10 2.02 QC- ACN- AA-XB 811

502.90 1.45 QC- ACN- AA-XB 812

475.10 1.60 QC- ACN- AA-XB 813

460.10 1.85 QC- ACN- AA-XB 814

474.20 1.95 QC- ACN- AA-XB 815

536.20 1.80 QC- ACN- AA-XB 816

446.20 1.62 QC- ACN- AA-XB 817

510.10 1.66 QC- ACN- AA-XB 818

489.50 1.54 QC- ACN- AA-XB 819

525.10 1.70 QC- ACN- AA-XB 820

487.90 1.94 QC- ACN- AA-XB 821

418.40 1.27 QC- ACN- AA-XB 822

404.40 1.16 QC- ACN- AA-XB 823

503.50 1.24 QC- ACN- AA-XB 824

501.13 1.08 QC- ACN- TFA- XB 825

515.60 1.00 QC- ACN- TFA- XB 826

500.90 1.13 QC- ACN- TFA- XB 827

502.90 1.15 QC- ACN- TFA- XB 828

487.30 1.35 QC- ACN- AA-XB 829

501.30 1.41 QC- ACN- AA-XB 830

460.90 0.98 QC- ACN- TFA- XB 831

481.60 1.30 QC- ACN- AA-XB 832

447.10 1.26 QC- ACN- AA-XB 833

446.50 1.02 QC- ACN- TFA- XB 834

501.20 1.42 QC- ACN- AA-XB 835

515.40 1.57 QC- ACN- AA-XB 836

501.10 1.00 QC- ACN- TFA- XB 837

503.20 1.57 QC- ACN- AA-XB 838

495.20 1.53 QC- ACN- AA-XB 839

503.00 1.64 QC- ACN- AA-XB 840

517.70 0.98 QC- ACN- TFA- XB 841

460.40 1.01 QC- ACN- TFA- XB 842

503.40 1.52 QC- ACN- AA-XB 843

517.00 1.51 QC- ACN- AA-XB 844

460.40 1.59 QC- ACN- AA-XB 845

538.30 1.66 QC- ACN- AA-XB 846

538.30 0.95 QC- ACN- TFA- XB 847

488.90 1.56 QC- ACN- AA-XB 848

489.20 1.56 QC- ACN- AA-XB 849

489.20 1.52 QC- ACN- AA-XB 850

503.20 1.41 QC- ACN- AA-XB 851

446.00 0.92 QC- ACN- TFA- XB 852

474.90 1.45 QC- ACN- AA-XB 853

489.30 0.92 QC- ACN- TFA- XB 854

501.10 1.69 QC- ACN- AA-XB 855

245.30 1.02 QC- ACN- TFA- XB 856

524.30 0.88 QC- ACN- TFA- XB 857

398.20 1.12 QC- ACN- AA-XB 858

483.10 0.78 QC- ACN- TFA- XB 859

489.20 0.78 QC- ACN- TFA- XB 860

517.00 1.60 QC- ACN- AA-XB 861

418.20 0.82 QC- ACN- TFA- XB 862

503.30 1.52 QC- ACN- AA-XB 863

503.20 1.38 QC- ACN- AA-XB 864

517.40 1.33 QC- ACN- AA-XB 865

460.40 1.66 QC- ACN- AA-XB 866

475.10 0.84 QC- ACN- TFA- XB 867

475.10 1.56 QC- ACN- AA-XB 868

538.20 0.93 QC- ACN- TFA- XB 869

538.10 1.64 QC- ACN- AA-XB 870

489.00 1.38 QC- ACN- AA-XB 871

503.40 1.42 QC- ACN- AA-XB 872

503.40 1.42 QC- ACN- AA-XB 873

503.40 0.87 QC- ACN- TFA- XB 874

517.10 1.10 QC- ACN- TFA- XB 875

517.00 2.03 QC- ACN- AA-XB 876

531.40 1.74 QC- ACN- AA-XB 877

503.00 1.10 QC- ACN- TFA- XB 878

517.50 1.48 QC- ACN- AA-XB 879

517.40 1.40 QC- ACN- AA-XB 880

545.40 2.02 QC- ACN- AA-XB 881

559.50 2.53 QC- ACN- AA-XB 882

545.20 1.85 QC- ACN- AA-XB 883

531.20 1.51 QC- ACN- AA-XB 884

418.30 1.23 QC- ACN- AA-XB 885

503.10 1.43 QC- ACN- AA-XB 886

517.00 1.02 QC- ACN- TFA- XB 887

489.40 0.85 QC- ACN- TFA- XB 888

483.00 1.26 QC- ACN- AA-XB 889

477.00 1.02 QC- ACN- TFA- XB 890

485.40 1.25 QC- ACN- AA-XB 891

491.30 0.76 QC- ACN- TFA- XB 892

529.50 1.39 QC- ACN- AA-XB 893

517.50 1.48 QC- ACN- AA-XB 894

531.50 1.00 QC- ACN- TFA- XB 895

531.00 1.72 QC- ACN- AA-XB 896

557.00 1.62 QC- ACN- AA-XB 897

503.30 0.86 QC- ACN- TFA- XB 898

517.30 1.46 QC- ACN- AA-XB 899

515.30 0.85 QC- ACN- TFA- XB 900

543.40 0.87 QC- ACN- TFA- XB 901

543.40 1.35 QC- ACN- AA-XB 902

517.30 1.37 QC- ACN- AA-XB 903

545.40 1.15 QC- ACN- TFA- XB 904

531.50 1.53 QC- ACN- AA-XB 905

531.40 1.59 QC- ACN- AA-XB 906

531.00 1.59 QC- ACN- AA-XB 907

559.00 1.75 QC- ACN- AA-XB 908

571.40 0.91 QC- ACN- TFA- XB 909

561.00 1.79 QC- ACN- AA-XB 910

559.50 1.64 QC- ACN- AA-XB 911

545.50 1.60 QC- ACN- AA-XB 912

545.50 1.04 QC- ACN- TFA- XB 913

515.40 0.90 QC- ACN- TFA- XB 914

559.50 1.52 QC- ACN- AA-XB 915

515.30 1.38 QC- ACN- AA-XB 916

517.30 0.81 QC- ACN- TFA- XB 917

519.20 1.51 QC- ACN- AA-XB 918

529.20 1.60 QC- ACN- AA-XB 919

537.40 0.90 QC- ACN- TFA- XB 920

555.40 1.36 QC- ACN- AA-XB 921

527.20 1.49 QC- ACN- AA-XB 922

515.20 0.93 QC- ACN- TFA- XB 923

529.40 0.96 QC- ACN- TFA- XB 924

543.40 1.00 QC- ACN- TFA- XB 925

573.50 1.49 QC- ACN- AA-XB 926

545.50 1.59 QC- ACN- AA-XB 927

517.20 0.84 QC- ACN- TFA- XB 928

529.30 1.51 QC- ACN- AA-XB 929

557.40 1.40 QC- ACN- AA-XB 930

575.00 1.75 QC- ACN- AA-XB 931

543.00 1.03 QC- ACN- TFA- XB 932

503.50 1.41 QC- ACN- AA-XB 933

517.20 1.48 QC- ACN- AA-XB 934

531.50 0.96 QC- ACN- TFA- XB 935

557.40 1.47 QC- ACN- AA-XB 936

529.50 1.44 QC- ACN- AA-XB 937

517.30 1.10 QC- ACN- TFA- XB 938

531.50 1.53 QC- ACN- AA-XB 939

545.10 1.73 QC- ACN- AA-XB 940

543.20 1.52 QC- ACN- AA-XB 941

515.30 1.50 QC- ACN- AA-XB 942

503.20 1.44 QC- ACN- AA-XB 943

517.00 1.07 QC- ACN- TFA- XB 944

531.30 1.59 QC- ACN- AA-XB 945

571.30 0.85 QC- ACN- TFA- XB 946

517.30 1.00 QC- ACN- TFA- XB 947

557.00 1.03 QC- ACN- TFA- XB 948

531.00 1.01 QC- ACN- TFA- XB 949

533.30 1.04 QC- ACN- TFA- XB 950

545.00 1.81 QC- ACN- AA-XB 951

577.20 1.01 QC- ACN- TFA- XB 952

464.00 0.98 QC- ACN- TFA- XB 953

561.20 1.65 QC- ACN- AA-XB 954

575.50 0.98 QC- ACN- TFA- XB 955

561.50 1.55 QC- ACN- AA-XB 956

543.40 1.35 QC- ACN- AA-XB 957

543.50 1.37 QC- ACN- AA-XB 958

571.20 1.55 QC- ACN- AA-XB 959

619.30 1.08 QC- ACN- TFA- XB 960

585.50 1.42 QC- ACN- AA-XB 961

585.30 1.09 QC- ACN- TFA- XB 962

579.30 1.92 QC- ACN- AA-XB 963

587.20 1.85 QC- ACN- AA-XB 964

506.30 1.54 QC- ACN- AA-XB 965

523.40 1.46 QC- ACN- AA-XB 966

515.60 1.01 QC- ACN- TFA- XB 967

517.60 0.91 QC- ACN- TFA- XB 968

487.20 1.46 QC- ACN- AA-XB 969

505.20 1.24 QC- ACN- AA-XB 970

475.50 0.92 QC- ACN- TFA- XB 971

545.40 1.25 QC- ACN- AA-XB 972

432.10 1.25 QC- ACN- AA-XB 973

416.10 1.29 QC- ACN- AA-XB 974

430.00 1.44 QC- ACN- AA-XB 975

223.90 1.28 QC- ACN- TFA- XB 976

418.10 1.07 QC- ACN- TFA- XB 977

418.10 1.08 QC- ACN- TFA- XB 978

402.10 1.01 QC- ACN- TFA- XB 979

416.10 1.31 QC- ACN- AA-XB 980

416.10 1.02 QC- ACN- TFA- XB 981

402.10 0.99 QC- ACN- TFA- XB 982

416.20 1.31 QC- ACN- AA-XB 983

432.10 1.19 QC- ACN- TFA- XB 984

402.10 1.01 QC- ACN- TFA- XB 985

402.10 1.32 QC- ACN- AA-XB 986

432.40 1.45 QC- ACN- AA-XB 987

420.00 1.27 QC- ACN- AA-XB 988

418.40 1.36 QC- ACN- AA-XB 989

404.40 1.25 QC- ACN- AA-XB 990

418.40 1.26 QC- ACN- AA-XB 991

418.20 1.50 QC- ACN- AA-XB 992

432.30 0.94 QC- ACN- TFA- XB 993

418.50 1.37 QC- ACN- AA-XB 994

420.00 1.20 QC- ACN- AA-XB 995

418.10 1.15 QC- ACN- AA-XB 996

502.30 0.81 QC- ACN- TFA- XB 997

503.30 0.81 QC- ACN- TFA- XB 998

524.20 0.82 QC- ACN- TFA- XB 999

418.10 1.00 QC- ACN- TFA- XB 1000

434.30 1.00 QC- ACN- TFA- XB 1001

364.00 1.09 QC- ACN- AA-XB 1002

449.10 0.79 QC- ACN- TFA- XB 1003

444.30 0.81 QC- ACN- TFA- XB 1004

473.90 0.99 QC- ACN- TFA- XB 1005

473.50 1.07 QC- ACN- AA-XB 1006

500.90 1.32 QC- ACN- AA-XB 1007

522.10 1.44 QC- ACN- AA-XB 1008

440.90 1.57 QC- ACN- AA-XB 1009

458.20 1.36 QC- ACN- AA-XB 1010

472.20 1.53 QC- ACN- AA-XB 1011

458.20 0.76 QC- ACN- TFA- XB 1012

486.20 0.79 QC- ACN- TFA- XB 1013

460.20 1.02 QC- ACN- TFA- XB 1014

455.10 1.44 QC- ACN- AA-XB 1015

444.20 0.83 QC- ACN- TFA- XB 1016

404.20 1.06 QC- ACN- AA-XB 1017

418.20 1.13 QC- ACN- AA-XB 1018

432.10 1.00 QC- ACN- TFA- XB 1019

446.20 1.32 QC- ACN- AA-XB 1020

446.20 1.27 QC- ACN- AA-XB 1021

476.20 1.23 QC- ACN- AA-XB 1022

415.10 1.35 QC- ACN- AA-XB 1023

443.20 1.46 QC- ACN- AA-XB 1024

485.20 1.44 QC- ACN- AA-XB 1025

485.20 1.37 QC- ACN- AA-XB 1026

507.30 1.46 QC- ACN- AA-XB 1027

971.40 1.51 QC- ACN- AA-XB 1028

473.10 1.34 QC- ACN- AA-XB 1029

472.30 0.93 QC- ACN- TFA- XB 1030

521.30 1.31 QC- ACN- AA-XB 1031

459.30 0.82 QC- ACN- TFA- XB 1032

475.30 1.45 QC- ACN- AA-XB 1033

529.40 1.27 QC- ACN- AA-XB 1034

503.00 1.43 QC- ACN- AA-XB

Example 10351-(aminomethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-ol

Intermediate 1035A:4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-1-(nitromethyl)cyclohexanol

To a 2 dram vial were added4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-one(0.200 g, 0.498 mmol), MeOH (5 mL), diethylamine (0.052 mL, 0.498 mmol)and nitromethane (0.269 mL, 4.98 mmol). Next, 20 μL of water was addedand the reaction mixture was stirred for 5 days at 25° C. The reactionmixture was concentrated under a stream of nitrogen gas, diluted withwater and stirred for 30 minutes. The white precipitate was filtered offand washed with water and dried through air to afford4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-1-(nitromethyl)cyclohexanol(0.200 g, 0.552 mmol, 100% yield) as a white solid. LCMS retention time0.64 min [Method A]. MS m/z: 363.2 (M+H).

Example 1035

To a Parr bottle were added4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-1-(nitromethyl)cyclohexanol,and 1:1 ethyl acetate: MeOH (7 mL). The vessel was purged with nitrogengas and 10% Pd-C (0.053 g, 0.050 mmol) was added. The bottle was placedon the Parr apparatus and pump/purged with nitrogen gas three times andback-filled with hydrogen gas. The reaction vessel was set to shake for6 hours at 40 psi. The reaction mixture was diluted with MeOH and thenfiltered through a pad of Celite and concentrated. The residue wassuspended in DMF (2 mL), filtered through a 0.45 micron nylon syringefilter. The crude material was purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate;Gradient: a 0-minute hold at 6% B, 6-42% B over 28 minutes, then a6-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fractions containing the product were combined and dried viacentrifugal evaporation to afford1-(aminomethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)cyclohexan-1-ol(0.8 mg, 0.00185 mmol, 0.4% yield), m/z (432.9, M+H). Retention time,1.253 min using LCMS Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM.¹H NMR (500 MHz, DMSO-d₆) δ 11.15-10.98 (m, 1H), 8.79 (s, 1H), 8.47 (s,1H), 7.60 (br d, J=8.5 Hz, 1H), 7.08-6.93 (m, 1H), 4.80-4.80 (m, 1H),3.33-3.19 (m, 1H), 2.91 (br d, J=7.0 Hz, 2H), 2.68 (br d, J=7.0 Hz, 3H),2.17 (s, 3H), 2.06-1.93 (m, 2H), 1.89 (s, 3H), 1.70 (br t, J=15.9 Hz,4H), 1.40 (br d, J=6.4 Hz, 8H).

The following examples were prepared according to the general proceduresdescribed in the above examples.

TABLE 3 Ex. Obs. QC No. Structure MS Ion RT Method 1035

433.10 1.24 QC-ACN-AA-XB 1036

470.30 1.27 QC-ACN-AA-XB 1037

487.30 0.75 QC-ACN-TFA-XB 1038

487.40 0.82 QC-ACN-TFA-XB 1039

487.40 0.82 QC-ACN-TFA-XB 1040

471.40 1.00 QC-ACN-TFA-XB 1041

473.20 1.38 QC-ACN-AA-XB 1042

473.40 1.39 QC-ACN-AA-XB 1043

535.10 0.99 QC-ACN-TFA-XB 1044

473.30 0.84 QC-ACN-TFA-XB 1045

473.30 1.01 QC-ACN-TFA-XB 1046

459.30 0.81 QC-ACN-TFA-XB 1047

514.40 1.22 QC-ACN-AA-XB 1048

459.00 1.08 QC-ACN-TFA-XB 1049

459.10 0.75 QC-ACN-TFA-XB 1050

514.40 0.87 QC-ACN-TFA-XB 1051

443.10 1.45 QC-ACN-AA-XB 1052

471.10 1.04 QC-ACN-TFA-XB 1053

533.50 0.56 A1 1054

459.50 1.54 QC-ACN-AA-XB 1055

485.50 1.45 QC-ACN-AA-XB 1056

459.10 1.48 QC-ACN-AA-XB 1057

485.20 0.81 QC-ACN-TFA-XB 1058

475.00 1.59 QC-ACN-AA-XB 1059

513.40 0.85 QC-ACN-TFA-XB 1060

499.10 1.41 QC-ACN-AA-XB 1061

499.40 0.83 QC-ACN-TFA-XB 1062

475.00 1.80 QC-ACN-AA-XB 1063

499.40 1.02 QC-ACN-TFA-XB 1064

473.00 1.82 QC-ACN-AA-XB 1065

499.20 1.61 QC-ACN-AA-XB 1066

513.50 0.85 QC-ACN-TFA-XB 1067

477.20 0.77 QC-ACN-TFA-XB 1068

501.30 0.78 QC-ACN-TFA-XB 1069

501.00 0.99 QC-ACN-TFA-XB 1070

501.00 1.00 QC-ACN-TFA-XB 1071

475.30 1.52 QC-ACN-AA-XB 1072

477.40 0.81 QC-ACN-TFA-XB 1073

501.30 0.79 QC-ACN-TFA-XB 1074

487.00 1.45 QC-ACN-AA-XB 1075

486.90 1.59 QC-ACN-AA-XB 1076

533.30 1.70 QC-ACN-AA-XB 1077

533.10 0.80 QC-ACN-TFA-XB 1078

403.10 1.43 QC-ACN-AA-XB

Biological Assays

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention.

TLR7/8/9 Inhibition Reporter Assays

HEK-Blue™-cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9receptors were used for screening inhibitors of these receptors using aninducible SEAP (secreted embryonic alkaline phosphatase) reporter geneunder the control of the IFN-β minimal promoter fused to five NF-κB andAP-1-binding sites. Briefly, cells are seeded into Greiner 384 wellplates (15000 cells per well for TLR7, 20,000 for TLR8 and 25,000 forTLR9) and then treated with test compounds in DMSO to yield a final doseresponse concentration range of 0.05 nM-50 μM. After a 30 minutecompound pre-treatment at room temperature, the cells are thenstimulated with a TLR7 ligand (gardiquimod at a final concentration of7.5 TLR8 ligand (R848 at a final concentration of 15.9 μM) or TLR9ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB andAP-1 which induce the production of SEAP. After a 22 hour incubation at37° C., 5% CO₂, SEAP levels are determined with the addition ofHEK-Blue™ Detection reagent (Invivogen), a cell culture medium thatallows for detection of SEAP, according to manufacturer'sspecifications. The percent inhibition is determined as the % reductionin the HEK-Blue signal present in wells treated with agonist plus DMSOalone compared to wells treated with a known inhibitor.

TABLE 4 TLR7/8/9 Reporter Assay Data (NT = not tested) TLR7 TLR8 TLR9Ex. IC₅₀ IC₅₀ IC₅₀ No. (nM) (nM) (nM) 1 20 3.8 7734 2 1.7 0.27 7325 30.93 1.1 8542 4 0.60 0.71 1072 5 471 4063 37 6 0.30 3.2 625 7 4.4 528124 8 4.7 21 8554 9 1.7 8.2 2248 10 0.42 5.3 1053 11 1.7 21 6794 12 101.6 10102 13 3.2 1.9 5020 14 11 4.2 4331 15 7.3 4.3 1940 16 0.60 2.1 63517 3.7 7.7 1097 18 14 14 1494 19 125 73 6023 20 2.7 1.3 614 21 9146 >50000 22 56 12 21148 23 >3125 >3125 >50000 24 40 2.7 13976 25 181117 11662 26 1769 2131 >50000 27 >3125 >3125 >50000 28 263 1496 >5000029 4.6 2.7 2832 30 70 43 22593 31 13 19 6059 32 7.3 6.9 1883 33 6.5 1.91915 34 17 6.0 1218 35 589 282 13783 36 >3125 >3125 22084 37 1269465 >50000 38 21 5.2 44362 39 40 4.8 NT 40 24 1.7 7956 41 264 177 >5000042 178 57 >50000 43 2.0 7.8 560 44 12 15 3374 45 22 20 7280 46 4.3 4.91682 47 NT NT NT 48 7.4 9.3 31274 49 1.0 0.62 2673 50 0.49 0.39 2839 515.1 7.0 16309 52 7.9 20 NT 53 0.62 0.23 1988 54 2.9 2.8 10376 55 2.10.39 3340 56 2.0 1.1 6340 57 7.4 1.3 5070 58 1.3 0.72 1969 59 1.3 1.12376 60 5.6 5.9 20242 61 4.4 1.8 2411 62 3.8 1.5 11497 63 7.4 4.0 4235764 3.8 1.6 5084 65 1.9 1.3 25112 66 1.4 0.98 3870 67 0.98 0.42 963 681.4 0.79 6300 69 1310 1314 25816 70 2.3 1.2 2967 71 99 31 3897 72 2.90.90 3416 73 29 5.7 24942 74 2468 2562 >50000 75 18 9.8 >50000 76 3415 >50000 77 4.8 2.0 11648 78 3.7 10 3171 79 373 355 9724 80 1.3 1.64558 81 1.3 0.95 20099 82 0.77 0.41 6376 83 3.6 6.9 5445 842196 >3125 >50000 85 1.8 5.8 5178 86 7.5 2.9 >50000 87 3.5 0.58 >5000088 68 91 3595 89 0.51 0.59 3258 90 0.57 4.2 4999 91 0.68 0.53 6311 920.87 0.78 3992 93 5.3 7.2 35043 94 1.0 1.4 9352 95 4.9 3.6 >50000 96 1.50.28 9430 97 28 4.1 >50000 98 0.74 0.72 5226 99 0.51 2.9 4303 100 3.20.55 6146 101 3.7 0.25 6402 102 12 5.1 >50000 103 7.3 2.6 NT 104 2.30.75 4161 105 3.9 0.15 9237 106 2.2 0.28 7779 107 2.2 0.37 5627 108 2.50.99 3512 109 3.6 1.3 8014 110 1.9 0.76 4544 111 NT NT NT 112 2.2 1.26009 113 1.4 0.95 3363 114 4.7 1.8 7590 115 1.2 0.49 3482 116 9.7 5.035642 117 1.4 0.81 5643 118 1.8 0.86 5581 119 1.8 0.96 14141 120 2.30.60 5487 121 3.4 0.80 6348 122 1.7 1.1 7251 123 1.9 6.3 8648 124 1.24.7 5786 125 2.6 0.66 6544 126 5.9 1.5 6117 127 4.6 0.48 5898 128 5.42.6 35374 129 6.7 1.3 22827 130 4.3 4.7 >50000 131 3.3 0.63 8572 132 2.80.51 7393 133 4.3 1.4 >50000 134 3.7 1.1 26146 135 4.7 1.6 13167 136 5.70.79 8223 137 5.6 1.3 8446 138 11 4.6 >50000 139 37 14 >50000 140 127186 >50000 141 134 148 >50000 142 107 45 >50000 143 7.8 4.5 >50000 1448.4 1.2 >50000 145 1.5 0.49 8201 146 5.6 2.5 12892 147 5.0 0.26 18656148 97 16 >50000 149 9.3 0.40 19497 150 12 2.7 >50000 151 1.2 1.2 11995152 2.7 1.6 5877 153 0.87 1.6 7150 154 1919 600 >50000 155 401 56 >50000156 1.5 0.79 6752 157 2.2 1.2 8844 158 2.3 0.96 8256 159 2.4 1.0 7735160 1.8 1.2 10645 161 1.4 0.92 5918 162 2.8 2.8 23098 163 9.7 5.0 24797164 33 2.0 19767 165 11 0.68 22656 166 1.5 18 2189 167 0.43 1.7 156 1680.89 3.4 658 169 3.1 21 1224 170 2.0 17 1411 171 0.45 1.8 560 172 1.9 131792 173 2.0 10 578 174 4.3 37 1468 175 0.35 2.0 926 176 5.2 84 16006177 0.28 2.5 148 178 0.48 1.8 895 179 0.92 7.0 1741 180 2.8 11 1871 1811.7 13 561 182 0.48 1.1 301 183 5.6 15 1031 184 8.8 18 2054 185 38 11010316 186 2.2 9.3 1011 187 2.1 20 4221 188 0.29 2.5 158 189 1.6 6.7 313190 0.80 2.8 353 191 0.90 2.7 202 192 3.1 19 1106 193 1.5 6.0 648 1948.6 47 3594 195 0.80 4.3 530 196 1.7 10 712 197 0.34 1.7 134 198 1.0 7.81142 199 0.16 6.4 1189 200 1.8 8.5 773 201 1.5 6.0 570 202 3.8 28 2030203 2.0 7.9 537 204 0.98 2.9 1332 205 0.42 1.0 134 206 9.5 22 2389 2071.9 4.4 253 208 2.2 16 1350 209 0.71 4.0 641 210 >3125 >3125 >50000 2111.1 6.8 585 212 3.4 6.8 1192 213 9.5 17 706 214 3.9 6.3 833 215 6.0 7.62254 216 5.1 18 416 217 5.0 8.6 522 218 8.5 20 389 219 3.9 8.0 2484 2206.7 6.1 1020 221 3.7 13 435 222 5.8 21 657 223 0.60 1.4 485 224 1.5 4.2718 225 4.0 35 3360 226 2.7 14 1790 227 2.0 7.7 926 228 3.3 23 2387 22919 18 1709 230 38 33 2460 231 0.61 3.0 365 232 3.0 9.8 484 233 11 242662 234 1.6 5.0 435 235 1.0 2.0 929 236 3.9 2.8 376 237 20 19 18183 2380.71 0.97 297 239 106 181 >50000 240 5.4 16 5076 241 2.0 2.9 1754 2421.5 15 2407 243 7.6 9.5 999 244 1.6 8.2 2349 245 2.7 4.7 343 246 1.9 2.64283 247 1.2 1.2 825 248 1.5 13 1785 249 25 7.3 5978 250 26 57 13721 2518.6 13 1754 252 8.0 10 7255 253 0.65 0.72 1149 254 72 27 8734 255 0.600.25 218 256 1.2 3.7 335 257 35 25 175 258 13 3.5 100 259 19 7.1 321 260527 173 10867 261 262 90 381 262 170 19 354 263 6.2 7.6 338 264 55 42255 265 0.59 0.91 392 266 45 13 322 267 1.9 2.6 453 268 94 32 578 269223 88 670 270 38 28 322 271 120 40 228 272 76 50 398 273 75 66 1114 2748.5 3.7 474 275 14 8.5 684 276 8.9 9.0 309 277 0.40 1.6 1378 278 1.5 1.2837 279 0.31 1.4 1817 280 1.1 7.2 1268 281 0.48 1.7 880 282 0.32 0.91661 283 0.92 1.4 298 284 3.0 15 4038 285 3.6 5.5 2310 286 5.2 9.2 1566287 25 33 2361 288 28 114 6454 289 3.5 11 967 290 2.1 6.3 425 291 2.6 11735 292 99 127 1615 293 75 208 5641 294 85 174 2270 295 11 11 883 2960.59 6.8 600 297 8.4 15 885 299 10 6.0 680 300 48 286 9048 301 2.0 424089 302 0.74 4.9 739 303 0.55 6.9 1233 304 0.53 1.8 1068 305 4.0 168237 306 13 61 10058 307 0.86 2.7 2978 308 11 11 3965 309 0.31 4.6 268310 0.39 4.1 1782 311 2.8 44 2017 312 0.26 1.6 577 313 0.21 7.0 1200 3142.4 47 5508 315 1.8 29 5223 316 1.4 41 3018 317 4.8 94 3611 318 0.17 2.11060 319 0.44 4.1 1690 320 1.0 22 1480 321 NT 3.0 1041 322 1.7 19 7409323 1.1 31 1357 324 6.6 240 20509 325 1.5 38 3110 326 0.13 3.7 988327 >3125 >3125 >50000 328 0.08 1.1 576 329 1.6 23 2066 330 0.14 4.82970 331 1.7 34 1914 332 1.3 88 2663 333 0.60 12 1456 334 4.6 127 2400335 NT 4.0 1927 336 2.8 48 3439 337 21 350 >50000 338 81 1170 >50000 3390.20 7.1 5888 340 1.4 51 1869 341 0.12 0.32 2643 342 0.98 3.9 1906 3430.19 0.54 1251 344 0.72 4.8 2789 345 0.21 0.68 1675 346 0.32 6.0 6294347 0.27 1.0 2466 348 0.82 8.3 6961 349 7.7 63 >50000 350 0.72 1.0 1155351 2.3 4.3 1688 352 5.4 9.2 2321 353 0.64 0.96 940 354 1.0 2.3 790 3552.6 10 4497 356 2.8 5.1 2865 357 3.9 4.4 1050 358 0.95 2.8 1325 359 9.129 4870 360 1.3 3.4 1414 361 0.79 1.0 1251 362 1.6 5.1 1634 363 3.3 6.61476 364 1.5 9.6 2523 365 4.2 7.9 3197 366 5.3 15 4693 367 1.5 3.5 838368 1.5 2.5 1612 369 0.46 1.3 402 370 8.6 23 >50000 371 6.0 14 4358 3723.2 7.6 1464 373 8.6 8.3 1956 374 36 187 21615 375 0.87 4.4 2716 3760.71 1.2 1027 377 2.1 2.2 767 378 1.6 4.6 1636 379 2.6 4.7 909 380 1.41.6 1878 381 3.7 5.5 8062 382 7.8 22 >50000 383 33 167 >50000 384 13 251526 385 22 46 11236 386 1.5 4.2 1440 387 7.2 19 5513 388 0.87 2.2 891389 0.45 1.6 923 390 1.6 7.6 3094 391 2.6 14 2451 392 3.2 6.1 1746 3930.47 1.3 360 394 1.4 1.5 1412 395 7.4 10 1621 396 1.7 17 1531 397 6.3 102402 398 3.8 17 4119 399 0.83 1.8 988 400 0.74 2.9 1549 401 5.7 6.4 5719402 31 43 5146 403 7.7 44 4281 404 3.8 9.3 1544 405 3.6 2.5 1425 406 1.43.0 1466 407 7.2 8.5 2457 408 18 43 6440 409 1.7 1.6 550 410 5.0 6.54925 411 6.3 8.0 2297 412 2.2 2.1 727 413 17 18 4737 414 5.1 12 1756 4152.5 3.5 1240 416 0.85 1.2 1622 417 5.2 7.1 9504 418 NT 3.9 2865 419 4.12.5 1744 420 1.2 2.8 3530 421 1.6 1.8 2058 422 15 35 6239 423 17583 >50000 424 0.89 0.74 1531 425 0.87 0.50 2915 426 2.5 2.6 1398 427 2.47.6 4904 428 7.4 6.4 9858 429 3.4 5.2 7002 430 13 14 15105 431 16 114657 432 0.37 0.55 584 433 42 60 >50000 434 1.5 2.4 7432 435 2.7 5.52176 436 8.9 27 8941 437 5.1 11 3752 438 0.77 0.39 1458 439 3.5 32 24228440 6.4 14 >50000 441 0.79 0.63 1660 442 3.7 3.5 18317 443 15 57 NT 44416 5.2 39175 445 1.5 3.6 4887 446 0.91 0.91 364 447 1.7 2.3 1637 448 7.524 7692 449 323 165 17986 450 0.61 0.71 1193 451 0.48 0.63 1045 452 2.74.4 3091 453 4.0 3.3 1440 454 1.2 0.68 2393 455 14 12 9203 456 2.6 8.17726 457 0.32 0.30 622 458 5.0 10 9840 459 6.2 4.3 2790 460 0.88 0.792063 461 2.6 1.7 8471 462 6.9 8.4 4538 463 7.4 24 16002 464 0.68 0.851774 465 1.1 1.9 5660 466 59 204 5796 467 1.2 3.5 413 468 46 99 NT 4690.98 2.9 1709 470 1.3 6.0 7422 471 2.8 3.2 4706 472 0.34 1.1 2511 4737.1 9.6 7373 474 0.46 0.43 1450 475 1.4 2.2 3504 476 0.81 2.6 9749 4778.3 6.0 6162 478 13 15 24545 479 2.9 10 23712 480 2.0 14 11749 481 0.823.9 13037 482 96 238 >50000 483 0.94 1.2 5126 484 6.1 11 7071 485 1.12.2 2516 486 1.2 1.9 2367 487 0.75 0.49 2289 488 11 8.4 5364 489 20 206674 490 1.2 3.4 2127 491 0.89 8.0 677 492 1.4 1.9 1478 493 17553791 >50000 494 5.2 2.8 14070 495 3.3 1.3 3603 496 7.5 2.1 2615 497 5267 >50000 498 NT NT NT 499 607 833 >50000 500 19 39 >50000 501 6.3 169553 502 0.79 5.1 2897 503 1.4 9.2 2503 504 0.55 0.64 3743 505 3.5 4.97601 506 0.41 0.42 3183 507 1.1 2.4 8492 508 1.1 3.3 6846 509 17 30 9105510 5.9 28 >50000 511 5.8 4.8 >50000 512 1.1 5.6 304 513 319 307 545 51438 44 7111 515 7.9 21 223 516 0.22 1.9 155 517 1.1 6.0 150 518 1.6 32721 519 8.3 12 362 520 0.80 7.0 285 521 0.62 1.3 238 522 2.6 495 144 5231.2 147 1470 524 0.88 6.7 407 525 0.18 48 771 526 8.8 14 666 527 7.3 3.01157 528 NT 23 5701 529 2.9 12 1833 530 7.1 8.8 4764 531 19 21 1289 5320.58 4.4 3594 533 0.50 3.3 1459 534 1.2 8.0 4276 535 2.0 8.6 5717 5360.66 4.1 2659 537 2.1 7.1 2853 538 2.0 3.3 8184 539 0.47 0.82 3322 — — —— 540 1.1 1.4 1951 541 1.2 0.36 1429 542 24 17 9235 543 14 5.3 2279 54411 6.4 5660 545 22 7.5 2464 546 9.5 1.6 1379 547 0.27 0.55 789 548 0.710.98 1090 549 1.8 18 401 550 0.87 15 796 551 0.94 5.5 582 552 0.83 2.14099 553 0.63 3.2 537 554 1.5 2.5 2861 555 0.85 3.0 341 556 1.7 1.1 5079557 0.66 1.2 440 558 1.2 5.6 3427 559 0.72 4.6 4923 560 1.2 1.0 3821 5610.64 3.0 5653 562 1.9 1.1 6484 563 0.83 2.4 4257 564 7.9 4.2 1764 5658.8 6.9 3224 566 24 18 18988 567 18 18 2325 568 6.0 3.8 2081 569 11 3.02183 570 10 57 143 571 7.5 2.1 813 572 4.6 25 1197 573 0.99 9.1 3234 5743.0 47 11936 575 0.44 121 1352 576 NT NT NT 577 0.69 7.4 1881 578 0.53287 4190 579 0.39 79 1838 580 0.41 8.7 1789 581 0.30 79 4920 582 0.99 127463 583 0.32 5.1 1552 584 0.24 29 2006 585 0.46 8.6 1839 586 0.75 982897 587 0.31 27 1408 588 2.3 42 16107 589 0.25 62 1062 590 3.0 4.7 3549591 4.8 7.7 2852 592 2.9 7.4 2244 593 1.4 2.6 974 594 3.9 16 7906 595122 >3125 10867 596 13 67 3204 597 1.3 1.2 918 598 0.81 3.1 949 599 2.74.8 3047 600 0.75 6.2 2051 601 46 46 >50000 602 1.2 6.8 1430 603 1.5 5.21190 604 2.8 2.5 5914 605 13 17 4244 606 2.3 3.9 1711 607 2.1 2.6 1142608 1.1 6.1 1713 609 2.6 23 2718 610 1.5 14 1771 611 8.4 17 1933 612 1356 3927 613 2.0 3.2 1243 614 1.9 13 1014 615 2.4 7.9 1958 616 3.6 1.51282 617 2219 1325 20509 618 4.8 4.6 3699 619 0.43 3.0 865 620 0.73 2.4223 621 7.0 7.5 14661 622 30 14 5071 623 1.6 2.0 3127 624 3.0 2.0 2568625 0.72 10 978 626 29 8.0 13454 627 7.9 18 4504 628 2.1 3.3 343 629 2.66.5 1920 630 1.9 14 1284 631 4.0 1.9 3067 632 3.1 2.2 439 633 40 3325537 634 2.0 3.0 2374 635 5.7 1.1 1785 636 46 28 21593 637 3.8 0.531359 638 2.9 7.3 1272 639 0.98 1.9 1472 640 4.9 4.9 13508 641 9.2 3.53344 642 14 26 18090 643 5.4 5.3 3170 644 2.7 4.5 2690 645 21 303 4087646 2.1 11 4140 647 2.3 26 5888 648 2.1 40 2073 649 6.2 10 3283 650 6.718 3125 651 1.7 24 687 652 3.0 22 1600 653 5.5 13 13221 654 6.4 9.6 4917655 1.4 11 2069 656 1.4 4.7 1853 657 2.1 10 842 658 3.8 8.2 13603 659 1224 8538 660 3.3 15 14410 661 2.3 5.5 13871 662 1.8 1.0 9030 663 3.5 9.921144 664 22 14 38509 665 34 17 >50000 666 0.73 1.6 6563 667 145711 >50000 668 1.7 22 17531 669 7.4 5.6 31553 670 56 58 >50000 671 1.42.1 4480 672 4.7 90 6244 673 5.2 6.9 14419 674 32 48 >50000 675 9.7 4.614462 676 1.0 2.5 5718 677 17 53 >50000 678 36 29 >50000 679 16 5.820652 680 12 5.2 1058 681 104 199 4236 682 16 24 1052 683 12 13 322 68414 13 365 685 32 39 1576 686 >3125 >3125 >50000 687 39 16 5774 688 8.423 177 689 11 42 433 690 15 31 288 691 11 9.2 315 692 43 58 1528 693 6.515 437 694 2309 2850 14611 695 42 20 3952 696 75 36 1311 697 20 111 919698 12 28 1004 699 12 46 430 700 26 43 2328 701 49 15 1748 702 41 142228 703 8.9 16 326 704 11 13 166 705 18 15 655 706 8.5 18 1020 707 1.55.3 1412 708 12 280 >50000 709 2330 >3125 >50000 710 2.0 3.2 4665 7112.0 2.9 1699 712 1.9 11 3145 713 6.2 28 4878 714 1.8 9.3 203 715 1.7 118707 716 0.74 6.7 2526 717 1062 1101 2525 718 9.6 3.6 6211 719 2.8 7.02596 720 13 94 20336 721 0.41 0.53 982 722 6.5 46 18477 723 0.99 2.44391 724 0.63 2.0 2194 725 0.62 1.9 2059 726 1357 2090 39366 727 3.6 3.23352 728 0.74 0.67 3538 729 1.1 1.3 1941 730 3.3 23 10526 731 4.6 151640 732 10 70 4834 733 53 1014 >50000 734 26 252 >50000 735 25 61 262736 631 269 >50000 737 0.59 0.55 7774 738 0.46 0.89 6226 739 0.85 1.65324 740 2.2 5.1 623 741 1.9 6.5 3034 742 2.9 3.1 4580 743 3.6 8.4 1881744 2.0 7.1 3058 745 2.2 5.8 2446 746 1.1 10 3106 747 0.59 4.1 7379 7487.5 15 37886 749 2.9 2.6 14893 750 1.2 3.7 6145 751 13 7.3 26035 7520.38 0.53 10266 753 3.8 12 27862 754 5.2 1.7 5432 755 2.8 6.2 3734 7563.9 6.0 9055 757 0.70 1.9 5215 758 0.89 1.7 18200 759 3.8 14 38197 7604.2 27 7629 761 9.0 14 8170 762 3.8 8.6 18318 763 3.8 2.6 4579 764 1.92.8 14428 765 5.6 3.5 10263 766 0.86 1.2 3512 767 5.4 2.9 8300 768 6.49.6 20957 769 1.3 4.5 5569 770 11 24 18183 771 4.3 9.2 9843 772 3.2 104713 773 3.0 4.6 2706 774 3.7 5.7 18596 775 3.8 4.4 8447 776 6.0 5.313088 777 9.2 7.4 14795 778 2.7 2.3 7908 779 7.3 11 34519 780 1.9 5.45225 781 11 18 14380 782 1.3 4.7 5736 783 1.8 3.9 8377 784 2.9 9.4 4527785 8.0 13 4684 786 7.7 12 14676 787 9.4 4.9 12254 788 2.1 3.2 8302 7893.2 3.7 13321 790 0.42 0.85 8810 791 5.3 1.1 18146 792 4.0 1.0 8555 7931.4 1.4 7829 794 1.4 1.5 18048 795 12 8.1 >50000 796 6.0 15 11322 797 1014 17578 798 4.2 5.7 22334 799 5.0 21 >50000 800 20 26 >50000 801 0.570.56 10960 802 3.0 0.65 17918 803 4.3 4.0 39663 804 1.2 0.56 18116 8052.1 0.57 24156 806 1.1 1.1 29426 807 0.95 1.3 16263 808 0.19 1.4 8946809 2.2 3.1 35999 810 0.64 0.63 7355 811 0.36 0.59 5596 812 2.23.6 >50000 813 3.7 9.1 >50000 814 1.9 2.3 >50000 815 1.8 1.4 >50000 8161.7 1.7 8723 817 2.1 2.9 >50000 818 0.78 0.43 12846 819 2.2 0.58 21064820 2.7 2.0 9396 821 1.3 1.3 6694 822 1.1 0.24 6914 823 0.49 1.2 6932824 1.6 2.1 5791 825 0.53 1.1 6277 826 0.70 1.0 15739 827 0.46 0.34 4852828 0.88 1.4 7157 829 3.7 12 17264 830 0.62 0.63 7443 831 1.5 2.3 8550832 4.0 2.3 16779 833 1.9 4.9 9782 834 0.46 2.5 4367 835 0.70 4.1 5560836 2.4 4.1 16449 837 0.70 1.6 7822 838 0.60 3.5 9891 839 0.37 3.2 7869840 0.38 1.5 7401 841 5.6 28 14253 842 0.38 0.47 6919 843 0.52 1.4 5479844 2.0 11 8817 845 7.2 14 21276 846 0.55 1.2 22620 847 4.9 8.3 22521848 1.2 2.2 17494 849 0.53 1.6 8120 850 0.72 1.6 6540 851 5.9 2.2 9978852 5.2 0.82 16163 853 0.51 0.66 9571 854 11 5.0 32272 855 2.4 4.6 14322856 7.3 0.46 27144 857 0.65 0.40 4396 858 1.1 1.3 7132 859 0.97 1.5 7308860 0.30 0.62 5062 861 0.31 4.2 5010 862 0.29 2.2 7037 863 0.52 17 6065864 1.5 12 5693 865 1.3 72 8891 866 3.2 74 47596 867 4.5 11 >50000 86812 6.1 >50000 869 1.9 34 40301 870 0.56 3.3 14448 871 1.6 5.1 12728 8720.97 3.8 9539 873 3.1 1.8 12788 874 1.2 5.3 15548 875 6.6 3.2 40475 876644 517 13255 877 1.5 1.6 12556 878 0.48 2.2 9042 879 1.0 3.4 7546 8806.4 30 19328 881 25 68 43465 882 3.3 11 7764 883 7.4 2.3 12546 884 0.900.17 6501 885 1.6 3.8 7846 886 2.8 1.7 2568 887 0.50 0.68 8121 888 1.20.59 12211 889 1.5 0.76 9839 890 1.8 1.4 14745 891 0.64 0.93 17965 8920.62 1.4 3285 893 0.34 0.74 7440 894 0.37 0.89 10763 895 0.74 1.1 7926896 0.69 0.37 8435 897 0.86 1.5 11982 898 2.1 3.2 17320 899 1.0 1.7 9780900 1.1 1.4 15593 901 0.72 0.15 13255 902 1.1 1.4 15789 903 3.0 4.135228 904 1.0 4.2 14798 905 0.51 0.82 12016 906 0.39 0.67 7799 907 0.760.45 >50000 908 0.89 0.26 6457 909 0.54 0.91 6707 910 0.68 0.86 5398 9110.68 1.5 7016 912 0.98 2.2 9330 913 1.0 1.8 8845 914 0.73 0.94 6046 9152.3 1.0 11137 916 18 11 14537 917 5.2 2.9 43171 918 3.2 6.3 20583 919 231.0 13895 920 2.6 5.9 12088 921 0.61 3.4 5267 922 0.55 2.1 9372 923 1.23.6 6556 924 1.7 4.9 7234 925 0.79 9.2 10082 926 3.3 3.0 3040 927 2.93.7 4357 928 1.5 6.9 3640 929 2.6 3.9 5086 930 22 7.4 24293 931 2.5 3.914927 932 0.66 10 14343 933 0.63 18 18442 934 0.86 8.6 9746 935 0.48 2.95613 936 0.56 3.5 4638 937 0.52 14 14243 938 2.6 4.9 8560 939 1.5 9.811863 940 1.7 0.66 8343 941 0.66 0.66 7198 942 0.50 3.4 12005 943 1.11.1 10046 944 3.1 4.9 17114 945 4.8 0.94 7846 946 1.4 1.8 8950 947 1.90.66 8773 948 2.8 1.4 12817 949 2.6 1.6 31028 950 7.2 4.9 36119 951 6.51.5 >50000 952 1.8 0.70 7862 953 0.92 5.3 12031 954 1.9 36 20896 9550.76 2.0 20450 956 1.0 1.9 9650 957 0.92 2.9 24415 958 0.27 2.3 11244959 1.4 0.29 7681 960 0.77 0.32 3166 961 0.35 0.80 8337 962 3.717 >50000 963 0.84 1.9 35268 964 0.53 0.25 3095 965 0.39 1.1 6483 9662.4 1.3 6022 967 7.9 1.2 38697 968 1.9 0.69 16436 969 1.3 0.12 7175 9703.1 0.92 10709 971 3.0 0.85 9246 972 3.3 3.1 6915 973 6.7 1.7 15804 9741.1 0.71 3918 975 12 0.61 6463 976 2.5 0.96 13425 977 1.4 2.1 8600 97811 1.8 11451 979 1.1 0.80 4291 980 2.2 2.3 6271 981 0.95 0.51 3066 9829.8 20 32827 983 0.82 0.12 6525 984 1.0 0.85 3427 985 1.6 1.1 3897 9860.63 0.38 2821 987 2.9 0.50 11253 988 0.36 0.23 3767 989 0.69 0.31 7098990 0.80 4.0 6024 991 0.27 0.32 5986 992 0.66 0.72 6311 993 0.82 1.57230 994 13 3.4 11830 995 0.56 0.48 7020 996 1.3 0.40 11011 997 2.4 2.413578 998 1.9 0.44 20008 999 7.5 2.1 10466 1000 18 3.2 6438 1001 70 4011739 1002 10 4.6 1099 1003 1.8 3.7 3164 1004 2.1 1.3 2794 1005 4.4 7.41659 1006 3.6 9.6 339 1007 3.2 4.0 2337 1008 15 32 13326 1009 4.5 7.72657 1010 3.6 4.7 2431 1011 11 22 23736 1012 0.59 1.4 1686 1013 11 9.27677 1014 21 26 21927 1015 1.3 7.8 2384 1016 2.9 38 641 1017 1.3 16 33021018 1.7 8.9 2782 1019 1.7 16 3278 1020 1.8 17 3863 1021 4.3 11 53291022 0.91 1.9 3650 1023 10 3.6 6939 1024 1.8 1.2 4538 1025 3.0 0.86 58611026 4.5 6.3 14488 1027 0.60 9.2 3003 1028 7.6 2.1 16992 1029 1.4 5.08378 1030 3.1 1.9 6278 1031 18 2.0 12671 1032 1206 196 25365 1033 1086974 22372 1034 1398 >3125 26595 1035 1.7 21 3666 1036 1.3 2.7 1931 10373.1 6.2 1609 1038 0.98 1.3 1910 1039 7.2 6.4 3068 1040 0.17 0.66 11061041 0.49 0.85 2424 1042 2.2 3.3 3316 1043 2.1 1.6 1749 1044 4.1 9.23595 1045 4.8 3.6 3236 1046 0.64 2.4 2502 1047 1.3 3.5 4493 1048 4.4 139827 1049 1.6 5.4 2599 1050 2.8 4.8 2657 1051 0.41 1.5 1908 1052 8.9 175920 1053 2.5 4.8 4807 1054 5.4 1.7 1692 1055 4.3 8.3 5471 1056 2.1 1.22992 1057 0.81 1.7 2698 1058 1.9 3.5 5275 1059 1.6 1.4 2247 1060 0.500.50 2598 1061 2.7 4.8 3175 1062 13 25 10182 1063 10 18 8057 1064 0.340.96 2455 1065 1.1 1.1 2796 1066 9.0 11 4291 1067 1.0 4.5 5396 1068 0.881.8 2957 1069 0.09 0.17 735 1070 0.54 0.72 845 1071 3.7 25 5951 1072 2.935 5841 1073 4.6 28 5832 1074 0.59 1.9 2126 1075 1.8 11 3354 1076 1.61.8 10583 1077 18 38 21801 1078 9.8 216 >50000In Vivo mouse TLR7 PD Model:

Adult male C57BL/6 mice were used for the experiments. Mice (7 to 10 pergroup) were randomized into different treatment groups based on bodyweight. Mice from the respective treatment groups were administeredorally with vehicle or test compound. Thirty min after the oraladministration of vehicle or test compound, mice were challenged withintraperitoneal injection of gardiquimod for TLR7 PD model. Ninetyminutes after gardiquimod injection, mice were bled under isofluraneanaesthesia and plasma IL-6 and IFN-alpha levels were estimated by usingcommercially available ELISA kit (BD Biosciences, PBL Life Sciences). Atthe end of experiment, mean cytokine data was plotted and one way ANOVAwith Dunnett's test was performed to calculate the significance of testcompound treated group vs. vehicle control group. Percent inhibition ofcytokine induction was calculated for test compound treated group vsvehicle control group. Data from multiple studies with different testcompounds is shown in Table 5.

TABLE 5 Percent inhibition of IL-6 and IFN-alpha in mouse TLR7 PD modelTLR7 PD model Dose % inhibition % inhibition Ex. No. (mg/kg) of IL6 ofIFN-alpha 3 0.005 0 29 0.01 24 37 0.05 75 94 0.25 90 99 0.5 91 100 40.0015 0 0 0.003 23 33 0.015 75 74 0.075 76 93 0.15 95 99 438 0.003 2536 0.006 41 57 0.03 56 67 0.15 78 96 0.3 82 98MRL/lpr Model of SLE:

Male MRL/lpr mice of 12-14 weeks age were screened and randomized basedon the titres of anti-dsDNA antibodies and urinary NGAL (NeutrophilGelatinase Associated Lipocalin). Mice were treated orally, once dailyfor 8 weeks with vehicle or test compound. The effect of test compoundon disease severity was assessed by measuring end points includingproteinuria, urinary-NGAL, urinary TIMP1, blood urea nitrogen (BUN),anti-dsDNA Ab, anti-smRNP Ab titer, and plasma levels of IL10 andIL12p40. At the end of experiment, all mice were euthanized by CO₂asphyxiation and kidney samples were subjected for histology. Tocalculate the significance of test compound treated group vs. vehiclecontrol group, one way ANOVA with Dunnett's test was performed. Percentreduction in disease severity was calculated for each parameter, fortest compound treated group vs vehicle control group. Data from a studywith test compound is shown in Table 6.

TABLE 6 Inhibition of disease development by TLR7/8 inhibitors inMRL/lpr model of lupus Dose Pro- Uri- Uri- Anti- Anti- Ex. (mg/ tein-nary nary SmRNP dsDNA IL- IL- No. kg) uria NGAL TIMP1 Ab titer Ab titer12p40 10 438 0.1 31 34 0 23 0 16 0 0.3 80 58 42 44 28 33 18 1 73 63 5449 39 26 19 3 82 67 56 43 44 28 21 10 84 67 79 51 37 41 22

What is claimed is:
 1. A compound of Formula (I)

N-oxide, or a salt thereof, wherein: G is

A is —O-L₁-R₆; L₁ is bond, —(CR_(x)R_(x))₁₋₂—,—(CR_(x)R_(x))₁₋₂CR_(x)(OH)—, —(CR_(x)R_(x))₁₋₂O—, —CR_(x)R_(x)C(O)—,—CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—,—CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, or—CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, R₁ is —CH(CH₃)₂; each R₂ isindependently —CH₃, —CH₂CH₃, —CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCH₃, —CH₂OCH₃,or —CH₂CH₂S(O)₂CH₃; each R₅ is independently F or —CH₃; R₆ is: (i) C₁₋₃alkyl, —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₃OH,—CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), or—CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂CHFCR_(x)R_(x)OH; or (ii)azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl, azetidinyl, C₃₋₆cycloalkyl, diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl,morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl,or quinuclidinyl, each substituted with zero to 3 R_(6a); each R_(6a) isindependently F, Cl, —OH, —CN, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₆hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl), —NR_(x)R_(x),—(CH₂)₁₋₂NR_(x)R_(x), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₃ alkyl),—(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x), —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(x),oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl,pyrrolidinyl, piperidinyl, isobutylpiperidinyl, piperazinyl, or—O(piperidinyl); each R_(x) is independently H or —CH₃; n is zero or 1;and p is zero, 1, or
 2. 2. The compound according to claim 1 or a saltthereof, wherein G is


3. The compound according to claim 1 or a salt thereof, wherein: G is


4. The compound according to claim 1 or a salt thereof, wherein: R₆ is:(i) C₁₋₂ alkyl, —CH₂C(O)NHCH₂CR_(x)R_(x)OH,—CH₂C(O)NHCH₂CH₂CR_(x)R_(x)OH, —CH₂C(O)NHCH₂CH₂NR_(x)R_(x), or—CH₂C(O)NHCH₂CHFCR_(x)R_(x)OH; or (ii) azabicyclo[3.2.1]octanyl,azaspiro[5.5]undecanyl, azetidinyl, C₃₋₆ cycloalkyl,diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl,tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl,piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zeroto 3 R_(6a); and each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x), —N(C₂₋₃alkyl)₂, —(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl,piperazinyl, or —O(piperidinyl).
 5. The compound according to claim 1 ora salt thereof, wherein: R₆ is: (i) —CH₃, —CH₂C(O)NHCH₂C(CH₃)₂OH,—CH₂C(O)NHCH₂CH₂C(CH₃)₂OH, —CH₂C(O)NHCH₂CH₂NH₂, or—CH₂C(O)NHCH₂CHFC(CH₃)₂OH; or (ii) azabicyclo[3.2.1]octanyl,azaspiro[5.5]undecanyl, azetidinyl, cyclohexyl,diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl,octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl,or quinuclidinyl, each substituted with zero to 2 R_(6a); and eachR_(6a) is independently F, —OH, —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂CH₂CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(CH₃)OH,—CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —NH₂, —N(CH₃)₂, —N(CH₂CH₂CH₃)₂, —CH₂NH₂,—CH₂CH₂NH₂, —CH₂CH₂S(O)₂CH₃, —CH₂C(O)N(CH₃)₂, —C(O)CH₂N(CH₃)₂, oxetanyl,tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, or —O(piperidinyl).6. The compound according to claim 1 or a salt thereof, wherein: A is—OR₆ or —O(CR_(x)R_(x))₁₋₂—R₆; R₆ is: (a) —CH₃; or (b) azetidinyl,cyclohexyl, or piperidinyl, each substituted with zero to 2 R_(6a); andeach R_(6a) is independently —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂, —CH₂C(CH₃)₂OH,—N(CH₃)₂, —N(CH₂CH₂CH₃)₂, —CH₂CH₂S(O)₂CH₃, —CH₂C(O)N(CH₃)₂, ortetrahydropyranyl.
 7. A compound, N-oxide, or a salt thereof, whereinsaid compound is selected from:6-(3-isopropyl-5-((1-methylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(590);6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(591);6-(3-isopropyl-5-((1-isopropylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(592);6-(3-isopropyl-5-((1-propylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(593);6-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine(594);6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(595);6-(3-isopropyl-5-((1-methylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(596);1-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-2-methylpropan-2-ol(597);6-(3-isopropyl-5-((1-isopropylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(598);1-(3-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)azetidin-1-yl)-2-methylpropan-2-ol(599);6-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(600);6-(3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(601);2-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-N,N-dimethylacetamide(602);6-(3-isopropyl-5-((1-isopropylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(603);6-(3-isopropyl-5-((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(604);4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dipropylcyclohexan-1-amine(605, 611);6-(3-isopropyl-5-((1-propylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(606);6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(607);6-(3-isopropyl-5-((1-methylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(608);2-(4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-N,N-dimethylacetamide(609);4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dimethylcyclohexan-1-amine(610);6-(3-isopropyl-5-((1-isopropylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(612);1-(4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-2-methylpropan-2-ol(613); and4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dimethylcyclohexan-1-amine(614).
 8. A pharmaceutical composition comprising a compound accordingto claim 1 or a pharmaceutically-acceptable salt thereof, and apharmaceutically acceptable carrier.
 9. A method for treating a diseasecomprising administrating to a subject in need thereof, atherapeutically-effective amount of at least one compound according toclaim 1 or a pharmaceutically-acceptable salt thereof, wherein thedisease is an autoimmune disease or a chronic inflammatory disease. 10.The method according to claim 9 or a pharmaceutically-acceptable saltthereof, wherein said autoimmune disease or chronic inflammatory diseaseis selected from systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), and Sjögren's syndrome.